Get Our e-AlertsSubmit Manuscript
Research / 2022 / Article

Review Article | Open Access

Volume 2022 |Article ID 9891689 | https://doi.org/10.34133/2022/9891689

Lexun Wang, Jiaojiao Feng, Yanyue Deng, Qianqian Yang, Quxing Wei, Dewei Ye, Xianglu Rong, Jiao Guo, "CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding", Research, vol. 2022, Article ID 9891689, 42 pages, 2022. https://doi.org/10.34133/2022/9891689

CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

Received14 Jul 2022
Accepted18 Sep 2022
Published07 Oct 2022

Abstract

CCAAT/enhancer-binding proteins (C/EBPs) are a family of at least six identified transcription factors that contain a highly conserved basic leucine zipper domain and interact selectively with duplex DNA to regulate target gene expression. C/EBPs play important roles in various physiological processes, and their abnormal function can lead to various diseases. Recently, accumulating evidence has demonstrated that aberrant C/EBP expression or activity is closely associated with the onset and progression of fibrosis in several organs and tissues. During fibrosis, various C/EBPs can exert distinct functions in the same organ, while the same C/EBP can exert distinct functions in different organs. Modulating C/EBP expression or activity could regulate various molecular processes to alleviate fibrosis in multiple organs; therefore, novel C/EBPs-based therapeutic methods for treating fibrosis have attracted considerable attention. In this review, we will explore the features of C/EBPs and their critical functions in fibrosis in order to highlight new avenues for the development of novel therapies targeting C/EBPs.

1. Introduction

Fibrosis, characterized by the excessive deposition of extracellular matrix (ECM) in the tissues, is not a disease but rather an outcome of the tissue repair response [1]. Fibrosis is a pathological hallmark of diseases in virtually any solid organ or tissue, which can be caused by diseases, physical and chemical stimulations, and trauma [2]. Multiple common diseases can lead to fibrosis, including diabetes, hypertension, myocardial infarction, heart failure, nonalcoholic steatohepatitis, hepatitis, idiopathic pulmonary disease, chronic kidney disease, scleroderma, and cancer. Persistent fibrosis can result in organ dysfunction and death. The annual incidence of fibrosis-related diseases is approximately 5% worldwide [3]. Moreover, fibrosis causes up to 45% of all deaths in the developed countries [1].

The inflammatory response plays a critical role in the initiation of fibrosis [2, 47]. In addition, the activation of ECM-producing cells is arguably a central event in fibrogenesis [8]. Although many cells can produce ECM, including 0fibroblasts, vascular smooth muscle cells, epithelial cells, and a subset of macrophages, activated fibroblasts (also referred to as myofibroblasts) are regarded as the principal ECM-producing cells as they generate numerous ECM components, including type I and III collagen [813]. Multiple complex molecular mechanisms are involved in fibrosis. For instance, transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), and integrins have been identified as important fibrosis regulators [1417]. Although some cellular and molecular processes underlying fibrosis have been elucidated in the past decade, few effective therapeutic strategies and drugs have been developed that can specifically target fibrogenesis [2, 14, 18]. These facts highlight the need for a deeper understanding of the pathogenesis of fibrosis and conversion of this knowledge into novel prophylaxis and treatment strategies.

CCAAT/enhancer-binding proteins (C/EBPs) are a family of basic region leucine-zipper (bZIP) transcription factor that dimerizes through a highly conserved C-terminal ZIP domain and bind to DNA through an adjacent basic region. To date, six members of this family have been identified and named in chronological order of their discovery: C/EBPα, C/EBPβ, C/EBPγ, C/EBPδ, C/EBPε, and C/EBPζ [1922]. The N-terminal of C/EBP proteins is more varied than the C-terminal. C/EBPα, C/EBPβ, C/EBPδ, and C/EBPε carry both activation and regulatory domains in their N-terminals [1922], whereas C/EBPγ and C/EBPζ lack activation domains and instead repress gene transcription by building inactive heterodimers with other members or transcriptional factors [21, 23]. Two isoforms of C/EBPα and three isoforms of C/EBPβ have been reported to function as activators or inhibitors depending on the number of activation or regulatory domains in N-terminal [20, 22]. In addition, C/EBPα expresses mainly in adipocytes, hepatocytes, and myeloid cells of hematopoietic system, whereas C/EBPβ has been detected in the adipose tissue, heart, liver, and brain [22, 24]. C/EBPγ and C/EBPζ ubiquitously express in most organs and tissues, but CEBPδ is expressed at low level in tissues and can be rapidly induced by stimuli [21, 25, 26]. C/EBPε is exclusively detected in myeloid cells [19]. The differences in CEBP expression profiles determine their important and unique roles in different tissues and organs. C/EBPs have been reported to affect various physiological processes, such as hematopoiesis, adipogenesis, energy metabolism, innate and adaptive immunity, inflammation, cellular proliferation and differentiation, apoptosis, and autophagy [21, 2329]. Consequently, aberrant C/EBP expression or activity can affect the occurrence and progression of various diseases, including cancers, Alzheimer’s disease, pneumonia, and cardiac infraction [23, 27, 3033]. Recently, an increasing number of studies have revealed that abnormal C/EBP expression and/or activation is closely related to the development of fibrosis in multiple organs [2326, 28, 3436]. For instance, protein levels of C/EBPα decrease in carbon tetrachloride- (CCl4-) induced fibrotic liver tissue, and overexpression of C/EBPα in the liver can alleviate CCl4-induced hepatic fibrosis [28, 37]. C/EBPβ expression is inhibited in diabetic cardiomyopathy- (DCM-) induced fibrotic heart tissue, and overexpression of C/EBPβ inhibits this cardiac fibrosis, while C/EBPβ knockdown attenuates heart fibrotic pathology in rat models of experimental autoimmune myocarditis (EAM) [34, 38]. The overactivation of C/EBPγ induced by IL-1β inhibits IL-6 expression in lung epithelial cells, which indirectly suppresses lung fibrosis [25, 39]. In the animal models, the C/EBPδ protein levels increased in kidney tissues during renal fibrosis [26]. Liver fibrosis is significantly reduced in C/EBPζ-/- mice after a bile duct ligation operation, whereas C/EBPζ-/- mice develops greater fibrosis than wild type mice when given a high-fat diet [40, 41]. In general, during fibrotic progression of a given tissue, C/EBPα and C/EBPγ play a negative role in fibrogenesis, while C/EBPβ, C/EBPδ, and C/EBPζ have positive roles [25, 4245]. A full overview of C/EBPs and their roles in fibrosis may be important to provide new therapeutic targets for treating fibrosis.

Here, we summarize the properties of C/EBP genes, proteins, and posttranslational modification (PTM). Then, we mainly review the crucial roles of C/EBPs in the fibrosis of different organs. Finally, we discuss current and future challenges in drug discovery and development of fibrosis therapies based on modulating C/EBP expression or activity.

2. Biological Features of C/EBPs

2.1. C/EBP Genes and mRNAs

Since the first C/EBP gene was identified and cloned from the rat liver tissue in 1988 [46], C/EBP genes have been cloned from various species and many of their proteins have been characterized and named independently, as summarized in Figure 1. It should be noted that C/EBPζ (also called CBF, CBF2, HSP-CBF, and NOC1) coded by Cebpz (gene ID: 12607 for mouse and 10153 for human) is excluded from the CEBP family as it lacks the bZIP motif and has low homology with other C/EBP members and is known as C/EBP homologous protein (CHOP, also known as growth arrest and DNA damage-inducible protein 153 (GADD153)) [20, 21, 29, 31]. For consistency, we referred to CHOP as C/EBPζ in this review.

C/EBPα, C/EBPβ, and C/EBPδ are encoded by single-exon genes, C/EBPγ and C/EBPε are encoded by genes with two exons, and Cebpz (Ddit3) contains four exons, two of which are within the 5 untranslated regions (5UTR). Athough there are only six genes, more than six C/EBP proteins can be present in tissues or cells. C/EBPα mRNA can produce two main polypeptides of 42 kDa (p42) and 30 kDa (p30), with the latter acting as an inhibitory isoform as it lacks the N-terminal transcriptional activation domain (TAD) [47]. Meanwhile, C/EBPβ mRNA can give rise to at least three isoforms: 38 kDa (full liver activation protein (LAP)), 35 kDa (LAP), and 20 kDa (liver inhibitory protein (LIP)). LAP and LIP are the major C/EBPβ forms in tissues and cells [48]. LAP contains both the activation and the bZIP domain, whereas LIP only possesses the bZIP domain and acts mainly as a negative inhibitor of C/EBPs by forming nontranscriptional active dimers with other C/EBP family members [48]. Some studies have reported that C/EBPε mRNA can be translated into at least four isoforms: 32, 30, 27, and 14 kDa. Notably, the 30 kDa isoform has a lower activation potential than the 32 kDa isoform, while the 14 kDa isoform acts as the negative inhibitor as it lacks the intact N-terminal TAD [27, 49, 50]. Since the NCBI database only contains one section of the protein sequence, we present a 32 kDa protein of C/EBPε containing 281 amino acids (aa) (Figures 1 and 2). On the molecular mechanism, different-sized C/EBPα and C/EBPβ polypeptides can be produced by using alternative translation initiation codons in the same mRNA due to an upstream open reading frame (uORF) positioned in the 5UTR [31]. Ribosomes scan the mRNA molecule from the 5-cap and begin translation at the first AUG; however, this AUG is skipped when translating the uORF and translation begins at a downstream AUG [51]. Alternatively, the C/EBPγ, C/EBPδ, and C/EBPζ mRNAs produce just one polypeptide.

2.2. C/EBP Proteins

The protein structure of C/EBPs has been studied extensively since the discovery of C/EBPα in the 1990s. All C/EBPs possess a highly conserved C-terminal (>90% sequence identity) containing a bZIP domain (Figure 2). The bZIP domain consists of a basic amino-acid-rich DNA-binding domain (DBD) and a leucine zipper (ZIP) dimerization domain that carries a heptad repeat of three (C/EBPε and C/EBPζ) or four (C/EBPγ) or five (C/EBPα, C/EBPβ, and C/EBPδ) leucine residues that adopt an α-helical configuration [52]. Dimerization is a necessary for bZIP factors to bind to DNA via the DBD; however, it is now accepted that C/EBPs do not recognize the CCAAT box, but instead recognize 5-(A/G)TT(G/A)CGAA(C/T)-3 consensus DNA sequences [20, 31, 5355]. The DBD also functions as the nuclear localization signal that mediates C/EBP translocation from the cytoplasm to the nucleus [56, 57]. Since the structure and DNA-binding characteristics of bZIP domains have been reviewed previously in excellent detail [29], we will not summarize these characteristics here.

The N-terminal region of C/EBPs is more varied than the C-terminal region. For instance, C/EBPγ and C/EBPζ lack activation domains and instead repress gene transcription by building inactive heterodimers with other members. Meanwhile, C/EBPα, C/EBPβ, C/EBPδ, and C/EBPε carry both activation and regulatory domains, allowing them to serve as activators [21, 22, 31, 47, 48]. However, in some contexts, C/EBPγ and C/EBPζ can also positively regulate transcription [5860]. Besides, multiple C/EBPα and C/EBPβ isoforms have been discovered (Figure 2) and have been reported to function as activators or inhibitors depending on the number of N-terminal activation domains [20].

In addition to dimerization with different C/EBP family members, C/EBPs can bind to other transcription factors and/or proteins in order to exert their functions. C/EBPs can not only dimerize with other bZIP transcription factors, such as Fos/Jun, cAMP response element-binding protein (CREB)/activating transcription factor (ATF) families, and/or AP1, but also interact with non-bZIP transcription factors including FOXOs, E2F, and NF-κB [20]. Furthermore, various enzymes, such as kinases, acetylases, and enzymes, related to ubiquitination can bind to some C/EBPs and regulate their transcription function. For instance, C/EBPα, C/EBPβ, C/EBPδ, C/EBPε, and C/EBPζ can be acetylated at different lysine residues to modulate their functions after binding to p300 [6165]. Some C/EBP isoforms can also interact with other proteins and perform nontranscriptional functions. For example, C/EBPδ can bind to the Fanconi anemia group D2 protein (FANCD2) and facilitate its nuclear import [66]. Proteins that interact with C/EBPs and the effects of their interactions are summarized in Table S1.

2.3. C/EBP Posttranslational Modification (PTM)

PTM is crucial for many cellular biochemical and physiological activities in both mammals and plants [6769]. Although hundreds of different types of PTM have been identified in eukaryotic proteomes, few have been studied extensively, including phosphorylation, acetylation, ubiquitination, glycosylation, methylation, small ubiquitin-like modifier modification (SUMOylation), and nitrosylation [70]. Before being translocated into the nucleus, C/EBPs undergo various PTM that can affect protein localization and stability, regulate DNA binding, and modulate interactions with transcription factors, cofactors, and other proteins [31]. Here, we mainly review C/EBP phosphorylation, acetylation, and SUMOylation, as well as ubiquitination and methylation (Figure 2).

Phosphorylation is the most common and well-studied PTM and is intimately involved in almost every cellular process. In particular, phosphorylation reversibly regulates protein activity through kinases and phosphatases [71, 72]. C/EBPα can be phosphorylated at S193 (serine at 193) by CDK4, which decreases its binding to C/EBPβ and enhances complex formation with histone deacetylase 1 (HDAC1) or p300, thereby increasing the transcription of fatty acid synthesis-related genes and inhibiting cell cycle-associated gene expression [7376]. The acetylation of lysine residues in nonhistone proteins plays a crucial role in many physiological functions, including protein folding and aggregation, RNA processing and stability, the cell cycle, and autophagy [70]. For example, the acetylation of C/EBPε K121 (lysine at 121) and K198 enhances its DNA-binding activity during neutrophil differentiation [77]. The ubiquitination of lysine or methionine residues can also affect many proteasome-independent functions, especially proteasomal degradation [78]. Indeed, C/EBPδ K120 ubiquitination by siah E3 ubiquitin protein ligase 2 (SIAH2) can promote its proteasomal degradation [79]. Though a similar biochemical process to ubiquitination, the SUMOylation of lysine residue can modulate many protein functions, such as subcellular localization, protein-protein interactions, and protein-DNA binding [80]. C/EBPδ SUMOylation at K120 by SUMO1 abolishes its interaction with p300, thereby inhibiting Cox-2 promoter activity [81]. The methylation of lysine or arginine residue plays an important role in protein stability, protein-protein interactions, protein-DNA interactions, and subcellular localization [82]. In C/EBPβ, R3 (arginine at 3) methylation not only interferes with the recruitment of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, and member 4 (SMARCA4), but also regulates myeloid and adipogenic differentiation [83, 84]. Meanwhile, C/EBPβ methylation at K39 inhibits the activation of myeloid genes and decreases its nuclear fraction [84, 85]. These C/EBP PTMs may play an important role in various diseases including fibrosis and be required to further study [19, 29, 31, 73].

2.4. C/EBP Location and Function

Although C/EBPs belong to the same family, their expression patterns can differ considerably. C/EBPα is highly expressed in numerous cell types, including adipocytes, hepatocytes, type II alveolar epithelial cells, and myeloid cells of the hematopoietic system [30], whereas C/EBPβ has been detected in the heart, liver, adipose tissue, kidneys, intestine, and lungs [31, 86, 87]. C/EBPγ and C/EBPζ are the ubiquitously expressed members of this family [25, 31]. Under normal physiological conditions, CEBPδ is expressed at low level in tissues and organs (except the liver, adipose tissue, intestine, lung, and brain) but can be rapidly induced by various events [31, 88]. C/EBPε is exclusively expressed in myeloid cells of the bone marrow [89].

These differences in the expression of CEBPs indicate that they play important and unique roles in different tissues and organs. C/EBPα mainly serves as a transcription factor that modulates adipogenesis, lung development, hepatocyte lipid metabolism, myelopoiesis, and myeloid differentiation [30, 75, 90, 91]. Thus, gene mutations that result in C/EBPα protein dysfunction play vital roles in malignant myelopoiesis, especially in acute myeloid leukemia (AML) [92]. And C/EBPa knockout mice die shortly after birth due to impaired energy homeostasis [93]. Similarly, C/EBPβ regulates the expression of genes involved in energy homeostasis and adipose tissue differentiation and affects endoplasmic reticulum (ER) stress and inflammation [94, 95]. Although some studies have reported that C/EBPγ exerts transactivation effects, it mainly functions as an inhibitor of C/EBPs and other interacted transcription factors [20, 25, 96]. Meanwhile, C/EBPδ transcriptionally modulates various biological processes such as cell differentiation, proliferation, motility, growth arrest, cell death, and inflammation depending on the cell type and cellular context [31, 32, 88]. Mice lacking C/EBPδ are viable, healthily, and exhibit no abnormalities, indicating that C/EBPδ is not vital for survival [53, 97]. In most cells, C/EBPδ expression is low under normal physiological conditions but can be rapidly induced by external stimuli [31]. Since C/EBPδ plays physiological roles in cell differentiation, proliferation, apoptosis, energy metabolism, and inflammation by regulating the expression of specific genes [31, 42], it may affect the pathogenesis of diseases such as fibrosis. Since C/EBPε is mainly expressed in hematopoietic cells, it is essential for the late myeloid lineage differentiation and the functions of neutrophils and eosinophils [27, 98]. Indeed, C/EBPε abnormalities are related to diseases such as neutrophil-specific granule deficiency (SGD), AML, and acute lymphoblastic leukemia [99101]. Finally, C/EBPζ has been reported to mediate ER stress-induced apoptosis [102] and regulate a wide range of genes involved in various cellular processes, such as inflammation, autophagy, and differentiation [21]. Thus, most C/EBP members can be detected in fibrosis-related cells such as fibroblasts, indicating that C/EBPs may play an important role in fibrosis.

3. Roles of C/EBPs in the Fibrotic Process

Increasing evidence has suggested that C/EBPs are closely associated with fibrogenesis [26, 40, 42, 90, 103, 104]. To date, several processes have been linked to the regulation of fibrosis by C/EBPs, including inflammation, lipid metabolism, cellular proliferation, apoptosis, autophagy, oxidative stress, ER stress, mitochondrial metabolism, macrophage polarization, and regulation of ECM gene expression. Here, we summarize the roles and mechanisms of C/EBPs in fibrosis.

It should be noted that there is no study about the role of C/EBPε in fibrosis so far. Several existing studies have shown that mice lacking C/EBPε display abnormal granulocyte terminal differentiation, decreased neutrophil infiltration into the lungs during ventilator-induced lung injury, and impaired phagokinetic motility of macrophages [105107], indicating that C/EBPε appears to participate in the onset and progression of multiple diseases by regulating the function of myeloid cells. Given the importance of myeloid cells in fibrosis-related diseases, further research should be required to elucidate the role of C/EBPε in fibrotic diseases.

3.1. C/EBPs in Liver Fibrosis

The liver is the critical hub of numerous physiological processes, including glucose and lipid metabolism [108, 109]; therefore, persistent liver dysfunction can affect the entire body and lead to diseases such as glycolipid metabolic disorder [109, 110]. Hepatic fibrosis, a pathophysiological result of two general types of chronic liver injuries: hepatotoxic injury and cholestatic injury, plays an important role in the development of various liver diseases through complex mechanisms [110, 111]. Fibrosis is the result of the interaction between varieties of cells. Myofibroblasts are the main source of ECM in hepatic fibrosis [14]. Hepatic stellate cells (HSCs) and portal fibroblasts are believed to be the major source of myofibroblasts in the fibrotic liver [112, 113]. In addition, it is now known that hepatocytes, macrophages, neutrophils, and mesenchymal stem cells also play the key roles in fibrosis [112]. This section review the roles of C/EBPs of these major cell types in liver fibrosis (Figure 3).

3.1.1. C/EBPα

Endogenous C/EBPα expression is high in the normal liver tissues [73, 114] but is typically found at lower levels during liver fibrosis and under other pathological conditions [90, 105]. Treatment with carbon tetrachloride (CCl4, commonly used drugs to induce cirrhosis in animals) has been shown to cause hepatic fibrosis and decrease C/EBPα level in the livers of mice [28, 37, 115]. Furthermore, C/EBPα overexpression reduces CCl4-induced hepatic fibrosis in mice [37], indicating that C/EBPα plays a vital role in hepatic fibrosis.

In HSCs, high C/EBPα levels are essential for maintaining its quiescent state [116, 117]. Numerous studies have shown that C/EBPα expression decreases during HSC activation and that enhanced C/EBPα expression inhibits the HSC activation [28, 90, 118]. Furthermore, C/EBPα overexpression has been reported to suppress HSC activation by upregulating the expression of target genes, including Albumin and adipogenic transcriptional factors (peroxisome proliferator-activated receptor γ (Pparγ) and sterol regulatory element-binding protein 1c (Srebp1c)]) [116, 117, 119, 120]. Similarly, SREBP1c overexpression inhibits α1 (I) procollagen expression and causes a phenotypic reversal from activated to quiescent HSCs [120]. High C/EBPα levels also induce HSC apoptosis in vitro and in vivo via two pathways: (1) the mitochondrial pathway (MP) and (2) the death receptor pathway (DRP) regulated by PPARγ and p53 [90, 121, 122]. In addition, C/EBPα has been reported to modify collagen maturation. miR-122 is a target gene of C/EBPα, and the levels of both are decreased in activated HSCs [123]. miR-122 overexpression inhibits HSC proliferation and markedly attenuates prolyl-4-hydroxylase alpha polypeptide 1 (P4HA1) expression by targeting a binding site in 3UTR of its gene, which hydroxylates the proline residue of collagen to allow its maturation [123]. C/EBPα overexpression also inhibits HSC proliferation by interacting with CDK2, CDK4, and E2F proteins [30, 118]. Together, this evidence indicates that C/EBPα levels correlate negatively with HSC activity and that C/EBPα upregulation could inhibit HSC activity and ECM production. Additionally, C/EBPα is involved in regulating HSC autophagy and a recent study showed that C/EBPα overexpression induces mitophagy in HSCs by binding to Beclin1 [124].

C/EBPα has been reported to function in terminally differentiated hepatocytes in the adult liver [90, 125]. C/EBPα overexpression inhibits hepatocyte proliferation by downregulating the expression of c-Myc and Cyclin D, reducing signal transducer and activator of transcription 3 (STAT3) phosphorylation, and improving liver function in a clinically relevant liver cirrhosis model [126, 127]. In addition, C/EBPα can regulate hepatic fibrosis through autophagy, with a recent study demonstrating that autophagy-related 16 like 1 (Atg16L1) is a target gene of C/EBPα in hepatocytes [128]. Atherogenic and high-fat diet-induced liver fibrosis mouse models display reduced C/EBPα and Atg16L1 expressions and increased liver fibrosis, while reversing high C/EBPα levels using peretinoin (an acyclic retinoid) increases autophagy activity [128]. A recent study showed that enhanced autophagy in the liver attenuates methionine-choline-deficient (MCD) diet-induced hepatic fibrosis and steatosis [129]. Conversely, inhibiting autophagy through hepatocyte-specific Atg5 or Atg7 deletion results in increased fibrosis in mouse livers [130, 131]. Furthermore, autophagy activation inhibits epithelial-mesenchymal transition (EMT) and hepatocyte differentiation into activated HSCs [132, 133]. During EMT, cells lose these epithelial characteristics, gain mesenchymal markers (e.g., vimentin, α-SMA, fibronectin, and fibroblast-specific protein 1), and express various collagens, resulting in increased ECM deposition [134].

C/EBPα also regulates iron metabolism in the liver to affect hepatic fibrosis. As one target of C/EBPα, hepcidin is thought to serve as a soluble modulator of iron metabolism by controlling intestinal iron absorption and iron release from macrophages [135]. Alcohol metabolism-mediated oxidative stress downregulates the expression and the DNA binding activity of C/EBPα in the liver, which reduces hepcidin levels in hepatocytes [136]. Low hepcidin levels cause iron overload in hepatocytes, which can increase the Fenton reaction to generate abundant reactive oxygen species (ROS) that cause grave cellular and tissue damage, thereby contributing toward fibrosis [137]. Besides, C/EBPα also regulates hepatic fibrosis by affecting the synthase and secretion of matrix-degrading proteases in hepatocytes. Cathepsin L (CTSL), a target of C/EBPα, is an extracellular matrix-degrading protease secreted by hepatocytes whose expression in hepatic cell lines is downregulated by acetaldehyde, an oxidative metabolite of ethanol [138]. In addition, decreased CTSL expression may partly contribute toward ECM deposition in alcoholic liver fibrosis [138, 139].

C/EBPα regulates the progression of hepatic fibrosis by modifying the secretory functions of neutrophils. For instance, liver fibrosis is alleviated and neutrophil numbers are increased in the liver of Tribbles pseudokinase 1- (Trib1-) deficient mice treated with CCl4 [24]. Trib1 plays an essential role in C/EBPα degradation by recruiting it to E3 ubiquitin ligase [24, 140], with C/EBPα expression reported to be upregulated in neutrophils in Trib1-deficient mice [141]. Further research has shown that C/EBPα overexpression directly induces matrix metalloproteinase- (MMP-) 8 and MMP-9 expressions and secretion from neutrophils, thereby mediating ECM degradation in the liver [24].

C/EBPα phosphorylation ar Ser193 in mice (p-C/EBPα-S193, S190 in human) plays an essential role in age-associated hepatic fibrosis. Aged livers are more susceptible to pharmacological therapies and are more likely to develop liver diseases such steatosis, cirrhosis, and fibrosis, at least partly due to increased p-C/EBPα-S193 caused by increased CyclinD3/CDK4 activity [73, 75, 142]. In aged livers, total C/EBPα protein levels are descended and p-C/EBPα-S193 levels are increased [73, 143]. P-C/EBPα-S193 upregulation in liver cells increases the formation of C/EBPα-p300 complex, which directly activates the promoters of triglyceride synthesis-related genes (diacylglycerol O-acyltransferase 1/2 (Dgat1/2), acetyl-coenzyme A (Acaca), stearoyl coenzyme A desaturase 1 (Scd1), and Srebp1), resulting in hepatic steatosis and fibrosis [75, 142, 143]. In addition, increased p-C/EBPα-S193 augments the C/EBPα-HDAC1 complex in aged liver under CCl4 treatment, which directly represses the promoters of Cebpα, Farnesoid X receptor (Fxr), and telomere reverse transcriptase (Tert) genes and disrupts the Rb-E2F1 complex, leading to increased apoptosis, accelerated liver cell proliferation (including HSCs), and the early development of liver fibrosis [73].

In summary, C/EBPα can negatively regulate liver fibrosis by regulating the functions of HSCs, hepatocytes, and other cells through various mechanisms. Notably, p-C/EBPα-S193 positively regulates age-associated hepatic fibrosis by affecting the formation and function of C/EBPα-p300 and C/EBPα-HDAC1 complexes.

3.1.2. C/EBPβ

C/EBPβ is detected in normal liver tissue but its protein levels or transcriptional activity decrease during various hepatic disease, including thioacetamide (a drug widely used for induction of fibrosis and acute liver failure)- or dimethylnitrosamine (DEN, a drug used to induce liver cirrhosis in experimental animals)-induced liver fibrosis, methionine-, and choline-deficient diet (MCD, used to induce nonalcoholic fatty liver disease)-induced liver fibrosis, CCl4-induced liver fibrosis, and streptozotocin (a drug can damage pancreatic beta insular cells)-induced diabetes [103, 144147]. C/EBPβ deficiency has been shown to inhibit CCl4-induced liver fibrosis [148]; however, other reports have shown that C/EBPβ protein levels or DNA binding activity increase in models of liver fibrosis induced by CCl4 [73, 149, 150]. Thus, C/EBPβ may play different roles in hepatic fibrosis.

HSCs are modulated by C/EBPβ activity [150]. One point is that high C/EBPβ levels or activity promotes HSC activation. C/EBPβ interacts with p300 to bind to the Col1α1 promoter and enhance its expression in HSCs induced by TGF-β1 or acetaldehyde [148, 151, 152]. Col1α1 stimulates further HSC activation and increases the phosphorylation-mediated activation of C/EBPβ-Thr217 (p-C/EBPβ-T217; Thr266 in human) [149, 153]. In addition, CCl4 upregulates p-C/EBPβ-T217 through increasing ribosomal S6 kinase (RSK), which inhibits caspase 8 (Casp 8) activation not only by interacting with p-C/EBPβ-T217 and proCasp8 but also by increasing the expression of Casp 8 and Fas-associated via death domain-like apoptosis regulator (CFLAR), a critical Casp 8 inhibitor, leading to decreased HSC apoptosis [149, 150, 153]. High p-C/EBPβ-T217 levels also promote HSC proliferation and activation, resulting in ECM production [150]. Alternatively, it has been reported that C/EBPβ negatively regulates HSC activation. When HSCs differentiate from quiescent lipid-storing cells into activated myofibroblasts to participate in liver fibrogenesis, C/EBPβ protein levels decrease [120]. It has shown that C/EBPβ can bind to the Tgf-b1 promoter and negatively regulate its expression [103]. Under DEN administration, the nuclear translocation of cytosolic C/EBPβ induced by oltipraz (5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione) inhibits TGF-β1 expression in HSCs, resulting in HSC inactivation and reduced ECM accumulation [103].

Hepatocyte C/EBPβ also plays different roles in liver fibrosis. ER stress increases C/EBPβ level in hepatocytes, which directly upregulates the expression of Sestrin2, a conserved antioxidant protein, thus resisting hepatocyte death [154]. A recent study showed that C/EBPβ levels decrease in hepatocytes induced by low FXR under DEN treatment, resulting in decreased C/EBPβ-HDAC1 complex formation [155]. This complex directly removes Gankyrin inhibition, leading to hepatocyte death through the Rac1/JNK pathway [155, 156]. Hepatocyte death is a key trigger for liver fibrosis progression; however, high C/EBPβ levels in hepatocytes can promote HSC activation by the C-C chemokine ligand 5 (CCL5) /CCR5 pathway. Lipid accumulation in hepatocytes also upregulates C/EBPβ, which binds to the Ccl5 promoter to increase its expression and secretion [157]. CCL5 subsequently binds to its receptor CCR5 in HSCs to boost their proliferation and collagen production [157].

Liver fibrosis also involves C/EBPβ expression in other nonparenchymal cells including Kupffer cells (the macrophages in liver). For instance, C/EBPβ levels are increased in miR-155 (its target gene Cebpb)-deficient Kupffer induced by lipopolysaccharide (LPS), resulting in M2 polarization and subsequent HSC activation through various mechanisms [158]. Besides, in the DEN-induced liver fibrotic/cirrhotic mouse model, increased C/EBPβ levels induce hepatic-sourced mesenchymal stem cell (MLpvNG2+) differentiation into hepatocytes (ALB+G6Pc+), thereby alleviating liver injury and inhibiting HSC activation [159].

In short, the roles of C/EBPβ in various cell types are different in the fibrosis process. Even in the same cell type such as HSCs, C/EBPβ effects on fibrosis are different under various stimuli. The possible reason is that the Cebpb gene can encode at least three isoforms with different functions in these cells. Future investigations should explore the roles of different C/EBPβ isoforms in various cell types during liver fibrosis.

3.1.3. C/EBPδ

Stimuli such as LPS, sepsis, endotoxemia, and partial hepatectomy can induce C/EBPδ expression in the liver tissue, indicating that C/EBPδ is involved in the hepatic diseases, including fibrosis [28, 160, 161]. It has been suggested that C/EBPδ may inhibit HSC activation, since C/EBPδ protein levels are decreased in activated HSCs but increased in quiescent HSCs [120]. Furthermore, treating HSCs with LPS or TNF-α can upregulate C/EBPδ, which binds to the Col1a1 promoter to inhibit its expression [28, 162]. Together, these studies illustrate that C/EBPδ plays an important role in limiting hepatic fibrosis via inhibiting HSC activation.

In hepatocytes, C/EBPδ expression can be stimulated by IL-1β and IL-6 [163, 164], and high C/EBPδ levels are maintained by autoregulation mechanisms through binding to the C/EBP sites located downstream of the Cebpd gene in HpeG2 cells [165]. In addition, IL-1β can elevate C/EBPδ levels and activate STAT3 in hepatocytes, which together upregulate hepcidin expression [163, 166]. High levels of hepcidin can prevent iron overload in hepatocytes, thereby reducing the development of hepatic fibrosis [137]. However, IL-6-stimulated C/EBPδ can be mediated by STAT3 and SP1 to bind to the plasminogen activator inhibitor-1 (Pai-1) promoter and upregulate its expression [164, 167]. Elevated PAI-1 levels inhibit plasmin-dependent MMP activity, thereby contributing toward the excessive accumulation of collagen and other ECM protein in tissue [168]. These data indicate that, although inflammatory cytokines can stimulate C/EBPδ expression, different inflammatory factors regulate different gene expressions through upregulating C/EBPδ, which can inhibit or promote liver fibrosis.

3.1.4. C/EBPζ

C/EBPζ was first identified during ultraviolet irradiation research [169]. Like C/EBPδ, C/EBPζ is extremely weakly expressed under normal physiology but is highly expressed under cellular stress [21]. Numerous studies have confirmed that C/EBPζ is the main executor of ER stress-induced apoptosis and regulates numerous genes involved in autophagy, differentiation, and inflammation [21, 117]. It has been suggested that C/EBPζ promotes fibrogenesis in the liver, as indicated by reduced hepatic fibrosis in mice lacking C/EBPζ under various stimuli [40, 170172]. However, some reports have shown that C/EBPζ exerts antifibrotic effects on the liver in vivo and in vitro [41, 173]. This may be due to the different responses of C/EBPζ in different liver cells under different stimuli.

The role of C/EBPζ in ECM-producing liver cells, including HSCs and liver fibroblasts, remains somewhat controversial. C/EBPζ upregulation caused by the deletion of heat shock protein 47 under autophagy inhibition or stimulation by cannabidiol can induce HSC apoptosis [174, 175]. Similarly, C/EBPζ upregulation induced by the accumulation of matricellular proteins can induce apoptosis in myofibroblasts derived from liver fibroblasts, which mitigates liver fibrogenesis by decreasing the cellular productions of fibronectin, Col1a1, and α-SMA [173]. However, increased C/EBPζ levels are observed in activated HSCs by cultured or treated with ER stress inducer, suggesting that C/EBPζ may play a role in HSC activation rather than apoptosis [176]. In addition, the upregulation of C/EBPζ induced by free fatty acids in liver fibroblasts directly inhibits Pgc-1a transcription and protein expression, which impairs mitochondrial steatohepatitis-associated circRNA ATP5B regulator (SCAR) expression, leading to ROS production and fibroblast activation [177].

Hepatocyte C/EBPζ promotes liver fibrosis. As a major player of ER stress, the upregulation of C/EBPζ induced by multiple stimuli can lead to hepatocyte apoptosis [178180]. Apoptosis is a frequent cellular process that causes organ remodeling and fibrosis in response to injury [21]. C/EBPζ directly activates apoptotic pathways by altering the transcription of proapoptotic or antiapoptotic genes and can directly bind to the dual-specificity phosphatase 5 (Dusp5) promoter and upregulate its expression, thereby decreasing ERK activity and leading to hepatocyte apoptosis under CCl4 treatment [178]. In addition, C/EBPζ upregulation induced by ER stress can directly increase the protein levels of NACHT, LRR, and PYD domains-containing proteins 3 (NLRP3), which can mediate inflammasome activation in hepatocytes, aggravating liver injury and fibrosis [181]. C/EBPζ can also induce hepcidin expression by inhibiting C/EBPα activation in hepatocytes treated with thioacetamide, resulting in a significant hepatic iron overload [182]. Alongside inflammasome activation, iron overload can aggravate hepatocyte damage, which in turn promotes liver fibrogenesis [137, 183].

The role of macrophages C/EBPζ in liver fibrosis remains inconsistent. For instance, high C/EBPζ levels are observed in F4/80+CD206+ macrophages (M2) during schistosomiasis-induced liver fibrogenesis [184] and C/EBPζ overexpression has been reported to stimulate M2 polarization through the KLF4/STAT6 pathway [185]. These data indicate that M2 macrophages induced by C/EBPζ play an important role in schistosomiasis-induced liver fibrogenesis. However, a recent report shows that C/EBPζ knockdown restores Arg1 and Mrc1 expressions, increases STAT3 and STAT6 activation, and enhances IL-10 secretion in Kupffer cells under hyperglycemic conditions, indicating that C/EBPζ is involved in high glucose-induced M1 macrophage polarization [186]. In addition, C/EBPζ-deficient bone marrow-derived macrophages resist apoptosis when treated with palmitic acid, leading to the accumulation of activated macrophages in the liver and subsequent liver fibrosis. Thus, macrophage C/EBPζ may protect the liver from fibrogenesis by limiting macrophage survival during lipotoxicity [41].

In summary, these existing studies about C/EBPζ in liver fibrosis show that C/EBPζ overexpression in profibrotic cells such as HSCs, fibroblasts, and M2 macrophages can lead to their apoptosis, inhibiting liver fibrosis, while its overexpression in nonprofibrotic cells such as hepatocytes and M1 macrophages can result in their apoptosis, promoting liver fibrosis by activating profibrotic cells.

3.2. C/EBPs in Lung Fibrosis

Lung fibrosis is a pathological process associated with various respiratory diseases, including immunological diseases (scleroderma and sarcoidosis), infection, and lung injury caused by chemicals, radiation, and environmental exposures [2, 112]. Pulmonary fibrosis is characterized by ECM deposition in interstitial and reduced lung compliance, and restrictive lung function and progressive lung fibrosis can lead to lung hypertension, right heart failure, and ultimately respiratory failure [2]. In addition to common molecular signaling pathways such as TGF-β, CTGF, Hedgehog, Notch, and fibroblast growth factor (FGF) [187], recent studies have shown that fibroblasts, alveolar epithelial cells, macrophages, Clara cells, and lung resident mesenchymal stem cell (LR-MSC) can been implicated in lung fibrosis through various mechanisms [14, 52, 188191]. Here, we discuss the roles of C/EBPs of these cell types in lung fibrosis (Figure 4).

3.2.1. C/EBPα

C/EBPα is expressed in various lung cells types, including alveolar type II cells, lung fibroblasts, alveolar macrophages, Clara cells, and bronchial smooth muscle cells [43, 91, 192, 193]. Under physiological conditions, C/EBPα regulates lung development and maturation [194, 195]; however, C/EBPα expression is markedly decreased in diseased lung or those subjected to harmful stimuli, indicating that C/EBPα plays an important role in the progress of pulmonary diseases, such as lung fibrosis [192, 196198].

Lung fibroblasts regulate tissue homeostasis and the balance between tissue repair and fibrosis. C/EBPα mRNA and protein levels are significantly decreased in fibroblasts isolated from the lung tissue of patients with idiopathic pulmonary fibrosis (IPF, a chronic progressive fibrotic disease) [43]. Furthermore, the siRNA-mediated loss of C/EBPα in normal lung fibroblasts enhances the profibrotic activation and ECM deposition, whereas C/EBPα upregulation by transient transfection in IPF-derived fibroblasts significantly reduces profibrotic genes expression and ECM production and while promoting lipid droplet formation [43]. Thus, C/EBPα could promote the dedifferentiation of myofibroblasts to fibroblasts to inhibit the lung fibrosis.

Recent evidence has suggested that the alveolar epithelium plays a central role in the pathogenesis of lung fibrosis [199]. Since C/EBPα has been detected in alveolar epithelial cells, C/EBPα may regulate the function of alveolar epithelial cells to affect lung fibrosis. However, the role of alveolar epithelial cell C/EBPα in pulmonary fibrosis is somewhat controversial. Didon et al. reported that epithelial-specific C/EBPα disruption results in the lung interstitial fibrosis, indicating that C/EBPα levels in alveolar epithelial cells correlate negatively with fibrosis [196]. Although no studies have examined the underlying mechanism, the disrupted dispersion of airway smooth muscle cells suggests that epithelial cells can transdifferentiate to mesenchymal cells [196]. However, Sato et al. have shown that conditional C/EBPα deletion in alveolar type II cells and Clara cells leads to the decreased fibronectin deposition [200]. In particular, C/EBPα regulates the protease/antiprotease balance by increasing the expression and activity of antiprotease to inhibit the protease activity in the lungs, which suppresses fibronectin degradation and lung fibrosis during the repair process [200], possibly due to the different effects of C/EBPα knockout in the lung tissue. Didon et al. constructed C/EBPα-knockout mice with Cebpafl/fl mice and Spc-Cre+ mice (surfactant protein C (SP-C) promoter active in all lung epithelial cells), in which the C/EBPα was deleted in all SP-C-expressed epithelial cells [196]. Sato et al. deleted Cebpa gene in the lungs using Scgb1a1-rtTA-/tg/(tetO)7CMV-Cretg/tg/Cebpafl/fl mice [200]. SCGB1A1 (secretoglobin family 1A member 1) is primarily expressed and secreted by the Clara cells [201]. Although C/EBPα was deleted in alveolar type II cells of these mice, its effect on positive regulation of lung fibrosis may be mainly mediated through Clara cells. Thus, further research is required to determine the precise function of C/EBPα in different cells, including Clara cells, during pulmonary fibrosis.

In brief, existing evidence shows that C/EBPα upregulation inhibits fibroblast activation by restraining α-SMA, FN, Col1a1, and CTGF expressions and suppresses the ECM production in alveolar epithelial cells through inhibiting its EMT and promoting the activity of antiprotease alveolar epithelial cells, indicating that targeting C/EBPα may be an effective strategy to treat pulmonary fibrosis.

3.2.2. C/EBPβ

In the lungs, C/EBPβ is expressed in parenchymal, mesenchymal, and infiltrated inflammatory/immune cells [42, 192, 202]. C/EBPβ protein levels or transcriptional activity are increased in lung tissues under various profibrotic stimuli, with C/EBPβ knockout inhibiting pulmonary fibrosis [39, 42, 190, 192]. Therefore, C/EBPβ may play an important role in lung fibrosis.

As a crucial fibrogenic factor, TGF-β1 can upregulate C/EBPβ protein levels in primary lung fibroblasts in vitro [203]. Compared to lung fibroblasts isolated from wild-type mice treated with bleomycin (common drug for inducing pulmonary fibrosis), lung fibroblasts isolated from bleomycin-treated C/EBPβ null mice exhibit lower α-SMA levels and greater proliferation ability [39]. Together, these studies indicate that C/EBPβ may regulate lung fibroblast activation. As a mediator of lung fibrosis activation, hypoxia can promote C/EBPβ phosphorylation at Thr266 (Thr217 in mice), which enhances its binding to a disintegrin and metalloproteinase 17 (ADAM17) promoter and ultimately induces ADAM17 expression in human lung fibroblasts [204]. ADAM17 overexpression in lung fibroblasts affects the hypoxia-induced expression of CTGF [204], which can induce Col1a1 and α-SMA expression by activating the Rac1/MLK3/JNK/AP-1 pathway [205]. Besides, hypoxia-induced C/EBPβ expression can upregulate antisense of hyaluronan synthase 2 (HAS2-AS1) in lung fibroblasts, which promotes HAS2 expression though HAS2 mRNA/HAS2-AS1 heterodimer formation [206, 207]. HAS2 is an enzyme responsible for the synthesis of the ECM component hyaluronan (also known as hyaluronate or hyaluronic acid (HA)). The overexpression of HAS2 and HA has been implicated in severe fibrosis [208]. In addition, the key inflammatory cytokine TNF-α can inhibit Col1a2 transcription in cultured fibroblasts by stimulating C/EBPβ protein expression [104]. However, C/EBPβ protein level is also induced by IL-1β in lung fibroblasts, with a greater increase in C/EBPβ-LIP isoform expression leading to a reduced LAP/LIP ratio and reduced α-SMA promoter activity and expression [209]. This may explain why treatment with inflammatory factors increases C/EBPβ expression and decreases fibroblast activation [210, 211].

In the alveolar epithelial cells, α-Sma and Ctgf are target genes of C/EBPβ [212, 213]. As an important factor in EMT, TGF-β1 increases C/EBPβ levels in alveolar epithelial cells and allows C/EBPβ to bind to α-Sma and Ctgf promoters and increase their protein levels [212, 213]. CTGF overexpression induces fibronectin expression in alveolar epithelial cells and increased α-SMA and fibronectin levels active the EMT, resulting in ECM deposition [212]. In addition, CTGF secreted from alveolar epithelial cells can activate the fibroblasts to produce ECM in a paracrine manner [205]. Thus, C/EBPβ may positively regulate the occurrence and development of pulmonary fibrosis in alveolar epithelial cells.

C/EBPβ expression in monocytes/macrophages is also involved in lung fibrosis. Recent studies have shown that C/EBPβ deficiency results in a complete lack of segregated nucleus-containing atypical monocytes (Ly6CF4/80Mac1+Ceacam1+Msr1+) derived from Ly6CFcεRI+ granulocyte/macrophage progenitors, preventing the development of bleomycin-induced lung fibrosis [190]. Moreover, high C/EBPβ levels in monocyte-derived alveolar macrophages, but not tissue-resident alveolar macrophages, promotes lung fibrosis [42, 214]. During lung injury, the stress response protein Trib3 in monocyte-derived alveolar macrophages interacts with GSK-3β and protects it from ubiquitination and degradation [214]. GSK-3β phosphorylates ubiquitin-editing enzyme A20 to inhibit its ubiquitin-editing activity, causing C/EBPβ accumulation in macrophages [42]. Activated C/EBPβ not only directly increases the transcription of Trib3 and Gsk-3b, thereby establishing a positive feedback loop in macrophages, but also enhances the expression of its targeted genes (Arg1, Il10, Tgfb1, and Fizz1) to promote a profibrotic macrophages (M2) phenotype and lung fibrosis [42, 214, 215].

In summary, these studies show that C/EBPβ upregulations of different cell types exert the profibrotic effect on pulmonary fibrosis. Given that LAP isoform is detected in most of these studies, C/EBPβ may play the profibrotic role through LAP isoform. Further research may be required to investigate the role of C/EBPβ-LIP isoform in the profibrotic effect of C/EBPβ in lung fibrosis.

3.2.3. C/EBPγ

C/EBPγ can only form stable heterodimerizes with other transcription factors, including C/EBPs, thereby regulating their transcriptional activities [216218]. Although C/EBPγ is involved in various cellular processes, such as the integrated stress response, cell proliferation, senescence, natural killer cell maturation, and glucose utilization [219222], there is no report about the role of C/EBPγ in the fibrogenesis. And a few studies have also focused on the role of C/EBPγ in regulating lung inflammation and wound repair. Since inflammation plays an important role in fibrosis, we will review the regulatory role of C/EBPγ in lung inflammation.

C/EBPγ can improve lung inflammation caused by a pathogenic stimuli, indicating that it may alleviate lung fibrosis. During acute lung injury induced by LPS and IgG immune complex, C/EBPγ overexpression in lung tissue alleviates pulmonary damage by reducing vascular permeability changes, decreasing the recruitment of neutrophils into alveolar spaces, and inhibiting the production of inflammatory mediators [223]. Mechanistically, C/EBPγ overexpression inhibits inflammation by reducing the transcription activities of C/EBPβ and C/EBPδ [223]. IL-1β induces C/EBPγ activation in lung epithelial cells, which attenuates the transcription activity of C/EBPβ and inhibits IL-6 expression [25]. IL-6 boosts lung fibrosis by not only activating pulmonary fibroblasts but also promoting M2 macrophage polarization [39, 224]. These reports indicate that C/EBPγ indirectly suppresses lung fibrosis through inhibiting inflammation.

3.2.4. C/EBPδ

In the lung, C/EBPδ is detected in alveolar type II cells, alveolar macrophages, Clara cells, and bronchial smooth muscle cells under physiological conditions [44, 225227]. C/EBPδ expression can be induced in lung tissue by multiple stimuli, including bacterial infections and LPS stimulation [33, 228230]; however, it remains unclear whether C/EBPδ directly regulates pulmonary fibrosis. Here, we discuss recent studies on the effect of C/EBPδ in alveolar type II cells, alveolar macrophages, Clara cells, and fibroblasts to illustrate its role in lung fibrosis directly or indirectly.

As a direct upstream transcription factor of IL-6 and TNF-α, C/EBPδ mediates the stimulation of these cytokines by LPS in macrophages during acute lung injury [44, 223]. In addition, inflammatory factors including TNF-α and IL-1β can induce the expression of C/EBPδ, which binds to the IL-6 and MCP-1 promoters and augments their expressions in alveolar type II cells [225, 231]. Various studies have shown that these cytokines participate in the regulation of pulmonary fibrosis. For instance, IL-6, a soluble mediator with a pleiotropic effects, can activate the STAT3/SMAD signaling pathway by binding to IL-6R in order to induce ECM expression in lung fibroblasts, thereby exacerbating bleomycin-induced lung fibrosis [224, 232, 233]. In addition to its role in monocyte recruitment to sites of inflammation, MCP-1 can stimulate ECM expression in lung fibroblasts by binding to its receptor CCR2 and endogenous upregulating TGF-β1 expression [234, 235]. Thus, C/EBPδ may accelerate lung fibrosis through indirectly inducing inflammatory cytokines in pulmonary epithelial cells and alveolar macrophages.

In Clara cells, C/EBPδ forms heterodimers with C/EBPα that can not only bind to C/EBP-response element sites in the Clara cell secretory protein (Ccsp) promoter to activate its expression but also enhance secretoglobin 3A2 (SCGB3A2) expression [236, 237]. In addition, C/EBPδ dimerizes with C/EBPβ to induce CCSP expression in Clara cells under glucocorticoid stimulation [238]. CCSP deficiency in obliterative bronchiolitis results in greater lung injury and fibrosis, indicating that CCSP inhibits lung fibrosis [239]. Meanwhile, SCGB3A2 exerts antifibrotic effects in bleomycin-induced pulmonary fibrosis by inhibiting TGF-β1-induced fibroblast activation via increased STAT1 phosphorylation and SMAD7 expression, and decreased SMAD2 and SMAD3 phosphorylation [240, 241]. These findings suggest that C/EBPδ can inhibit pulmonary fibrosis through upregulating secretory proteins in Clara cells.

Therefore, C/EBPδ upregulation in alveolar epithelial cells and macrophages can promote lung fibrosis through activating fibroblasts. However, C/EBPδ upregulation in terminal bronchiole cells (Clara cell) could inhibit lung fibrosis by different mechanisms. These findings indicate that C/EBPδ in different regions of lung tissue could play different roles in fibrosis process.

3.2.5. C/EBPζ

C/EBPζ expression is increased in the lung tissues of patients with IPF [45, 242] and can be upregulated by multiple stimuli, including bleomycin, hypoxia, and silica, to induce lung fibrosis [45, 243, 244]. Although these studies suggest that C/EBPζ may play an important role in the occurrence and development of pulmonary fibrosis, growing evidence has shown that C/EBPζ does not exert the same effect on pulmonary fibrosis in different lung cells.

In the lung tissues of IPF and pulmonary fibrosis models, C/EBPζ is mainly located in alveolar epithelial cells [242, 245]. ER stress caused by multiple stimuli such as hypoxia and increased hypoxia inducible factor-1α (HIF-1α) can upregulate C/EBPζ in alveolar epithelial cells, which subsequently promotes the expression of proapoptotic genes and inhibits antiapoptotic genes, leading to apoptosis and potential organ remodeling and fibrosis [21, 45, 242, 243]. In addition, ER stress-induced C/EBPζ upregulation can increase Sonic Hedgehog expression and promote its secretion from type II alveolar epithelial cells, which then activates lung fibroblasts through activating the Hedgehog signaling pathway and polarizes macrophages into the M2 stage in an osteopontin-dependent manner, resulting in pulmonary fibrosis [246, 247]. Furthermore, increased C/EBPζ levels can exacerbate lung fibrosis by inducing senescence in alveolar epithelial cells [248]. In vivo and in vitro studies of bleomycin and tunicamycin (a drug is employed to induce ER stress) have shown that C/EBPζ upregulation can induce alveolar epithelial cell senescence through the ROS/NF-κB pathway, which activates lung fibroblasts mediated by the senescence-associated secretory phenotype, promoting a pulmonary fibrosis pathology [248, 249].

C/EBPζ is mainly involved in the activation of lung fibroblasts. Thrombin, SiO2, and bleomycin can induce the ER stress via the PI3K/AKT/mTOR pathway to stimulate the upregulation of C/EBPζ protein, which activates lung fibroblasts [244, 245, 250]. Increased C/EBPζ levels also induce lung fibroblast apoptosis, but to a lesser degree than their proliferation, resulting in increased cell numbers [244, 251]. In addition, lung resident mesenchymal stem cells (LR-MSCs) can transform to myofibroblast to promote lung fibrogenesis [252]. C/EBPζ overexpression caused by ER stress or exogenous DNA facilitates transformation of LR-MSC into myofibroblast induced by TGF-β1, which binds C/EBPβ to eliminate TGF-β/SMAD signaling pathway-mediated inhibition [253].

Despite these findings, the role of macrophage C/EBPζ in pulmonary fibrosis remains unclear. Although C/EBPζ is primarily detected in alveolar epithelial cells under fibrotic stimuli, it is also expressed in lung macrophages [254]. Bleomycin-induced pulmonary fibrosis is found to be significantly attenuated in C/EBPζ-deficient (C/EBPζ-/-) mice; however, the number and polarization of alveolar and interstitial macrophages does not differ significantly after bleomycin treatment, indicating that C/EBPζ expression in lung macrophages has no effect on pulmonary fibrosis [45]. However, a recent report has shown that bleomycin treatment in C/EBPζ-/- mice results in lung ECM deposition associated with an increased number of Arg1-positive macrophages (M2) that activate lung fibroblasts, indicating that C/EBPζ can inhibit M2 polarization to alleviate lung fibrosis [97]. Conversely, another recent study has shown that C/EBPζ deficiency represses M2 macrophage polarization in lung tissues during bleomycin-induced pulmonary fibrosis, thereby attenuating TGF-β1 secretion [254]. In particular, C/EBPζ loss promotes SOCS1 and SOCS3 expressions to repress the STAT6/PPARγ signaling, which is essential for M2 macrophage polarization [254]. The varying role of macrophage C/EBPζ in lung fibrosis may be due to differences in processing, indicators of macrophage polarization, and detection methods. Therefore, further studies should investigate the role of macrophage C/EBPζ in pulmonary fibrosis.

In short, although C/EBPζ is mainly located in alveolar epithelial cells with profibrotic effect on lung, C/EBPζ in fibroblasts, LR-MSCs, and macrophages are participated in regulation of lung fibrosis through various signaling pathways.

3.3. C/EBPs in Kidney Fibrosis

Kidney fibrosis is the mainly histopathologic manifestation of various chronic kidney diseases (CKDs). Various pathophysiologic characteristics underlying kidney fibrosis are shared with other fibrotic diseases such as cirrhosis and IPF, including injury, inflammation, myofibroblast activation and migration, and ECM deposition and remodeling [255]. In addition, tubular epithelial cells (TECs) and macrophages can promote renal fibrosis through EMT and macrophage-to-myofibroblast transition (MMT), respectively [256, 257]. Mesangial cells, podocytes, and collecting duct epithelial cells (CDECs) are also involved in kidney fibrosis under various stimuli [36, 226, 258]. C/EBP proteins are expressed in these cells and involved in their regulatory effects in renal fibrosis. This section reviews the roles of C/EBPs in these cells to kidney fibrosis (Figure 5).

3.3.1. C/EBPα

C/EBPα is broadly expressed in the kidneys [259], indicating that it may also play an important role in renal fibrosis. Similar to fibrosis in other organs, fibroblast activation is a central event in renal fibrogenesis [8]. Aristolochic acid, a botanical toxin associated with the development of renal fibrosis, upregulates the DNA binding activity of C/EBPα through the AKT/mTOR pathway in kidney fibroblasts [260]. Increased C/EBPα activity, not protein expression, directly upregulates the expression of Leptin [260], which is considered a cofactor of TGF-β activation that enhances the TGF-β signaling in normal rat kidney fibroblasts [261]. Thus, C/EBPα expression in fibroblasts indirectly and positively regulates the renal fibrosis.

A recent study shows that C/EBPα is mainly expressed in podocytes [259]. Podocyte-specific C/EBPα deletion exacerbates renal fibrosis caused by aging [36], indicating that C/EBPα in podocytes can inhibit age-induced renal fibrosis. In addition, C/EBPα deletion in podocytes aggravates their senescence while C/EBPα overexpression inhibits podocyte senescence induced by adriamycin (also known as doxorubicin, an anticancer drug) [36]. In aging mice, podocyte senescence worsens glomerulosclerosis and subsequent albuminuria exacerbates senescent tubular cell EMT by suppressing autophagy, resulting in renal fibrosis [36]. C/EBPα overexpression also reduces adriamycin-induced increases CTGF mRNA expression in podocytes [36]. Secreted CTGF can activate surrounding fibroblasts that synthesize and secrete ECM, thereby promoting the occurrence and development of fibrosis [262]. Together, these studies indicate that C/EBPα in podocytes inhibits kidney fibrosis through various manners.

C/EBPα in CDECs is also involved in tubulointerstitial fibrosis. A previous report has shown that C/EBPα regulates the transcription factor Krüppel-like factor 5 (KLF5) during kidney inflammatory responses to injury [263]. KLF5 is mainly expressed in CDECs, and KLF5 haploinsufficiency in CDECs reduces the protein level of C/EBPα, thereby inhibiting KLF5/C/EBPα complex formation [263]. This complex induces the production of the chemotactic proteins S100A8 and S100A9, which drive monocytes to the kidneys and encourage their polarization into M1-type (CD11b+F4/80lo) macrophages [263]. M1 macrophages inhibit fibrosis in multiple organs not only by secreting MMPs to directly degrade ECM but also by secreting inflammatory factors to inhibit fibroblast activation and reduce ECM synthesis [264, 265]. Thus, C/EBPα expression in CDECs may inhibit renal fibrosis caused by unilateral ureteral obstruction (UUO, a common form of upper urinary tract obstruction can lead to fibrosis) [42].

Together, these studies suggest that C/EBPα can positively or negatively regulate the pathological process of renal fibrosis in different cells through various indirect ways. Further studies may be required to elucidate the roles of C/EBPα in different cell types of kidneys during physiological and pathological processes, including renal fibrosis.

3.3.2. C/EBPβ

C/EBPβ level is decreased in the kidney tissue of animal models of fibrosis, including diabetic nephropathy and UUO model [266268], indicating a negative correlation between C/EBPβ levels and renal fibrosis. In TECs stimulated with TGF-β1, TNF-α, H2O2, or high glucose, the protein levels or transcriptional activity of C/EBPβ and its targets genes, including Pgc1a, Klotho, tubulointerstitial nephritis antigen (Tinag), and suppressor of cytokine signaling 3 (Socs3) are decreased [87, 266268]. Decreased PGC-1α levels in TECs from mice with UUO cause mitochondrial dysfunction and ROS production, leading to EMT and subsequent ECM production [188, 269]. In addition, EMT and ECM production can be promoted by Klotho downregulation by miR-34a in UUO mice, which eliminates its inhibition of FGF2, TGF-β1, and Wnt signal pathways in TECs [270]. High glucose levels decreased SOCS3 in TECs, thereby removing the inhibition of STAT3 activation, increasing monocyte chemoattractant protein-1 (MCP-1) production, and inducing monocyte infiltration into the kidneys [266]. Meanwhile, bone marrow-derived macrophages from injured kidneys can be converted into α-SMA+ myofibroblasts through the MMT, thus contributing toward pathogenic collagen production during kidney fibrosis [5].

In addition, C/EBPβ expression is elevated during IL-4-induced M2 polarization of macrophages [271]. C/EBPβ overexpression has been reported to rescue decreased Arg1, Ym1, and Fizz1 expressions in TSC complex subunit 1- (TSC1-) deficient macrophages treated with IL-4 [189]. These reports indicate that C/EBPβ regulates macrophage M2 polarization. M2 macrophages can promote renal fibroblast activation by secreting fibrogenic factors such as IL-10 and TGF-β1 [271].

In brief, C/EBPβ upregulation in TECs inhibits renal fibrosis through various mechanisms, while increased C/EBPβ proteins in kidney macrophages can induce M2 polarization to activate fibroblasts, thus promoting fibrosis.

3.3.3. C/EBPδ

Previous studies have shown that C/EBPδ levels are increased in kidney tissues from animal models of UUO, diabetic nephropathy, and hypoxic kidney [26, 272, 273], which are closely related to renal fibrosis, indicating that elevated C/EBPδ levels may participate in kidney fibrogenesis. In TECs, C/EBPδ expression is induced by high glucose, IL-1β, or hypoxia via the NF-κB pathway and then directly binds to the Hif-1a promoter and enhances its expression [272, 273]. High HIF-1α levels promote renal interstitial fibrosis by inducing EMT in TECs [272]. In mesangial cells, C/EBPδ levels are upregulated by various factors, including IL-1β, LPS, TNF-α, and PDGF [274, 275], and can mediate their trans-differentiation into myofibroblasts by directly upregulating α-SMA expression, thereby promoting the progression of renal fibrosis [276]. In addition, high C/EBPδ levels in mesangial cells can induce the expressions of IL-6 and MCP-1 [275], which participate in renal fibrogenesis through multiple mechanisms including activating fibroblasts [277, 278]. Together, these studies indicate that C/EBPδ upregulation in TECs and mesangial cells can promote the occurrence and development of renal fibrosis.

3.3.4. C/EBPζ

Under normal physiological conditions, C/EBPζ is mainly expressed in renal tubular epithelial cells [279]; however, C/EBPζ is upregulated in tubular epithelial cells and glomerular endothelial cells under injury stimuli [279281]. Accumulating evidence has shown that C/EBPζ expression is upregulated in fibrotic kidney tissues from patients with chronic kidney diseases and obesity, and in animal models of kidney injury, C/EBPζ deficiency attenuates renal fibrosis in mouse model UUO, Ang II/deoxycorticosterone acetate/salt, and diabetic nephropathy [279, 282285]. These studies suggest that C/EBPζ can promote kidney fibrogenesis.

Various in vivo and in vitro studies have shown that decreased C/EBPζ expression caused by C/EBPζ gene loss, siRNA, or ER stress inhibitors alleviates the apoptosis of renal cells, macrophage infiltration in kidney tissue, and TGF-β1 expression [282, 283, 285, 286]. Mechanistically, C/EBPζ upregulation promotes renal fibrosis through apoptosis and C/EBPζ expression induced in renal tissues by UUO can activate the HMGB1/TLR4/NF-κB signaling pathway to stimulate IL-1β production, which enhances TGF-β1 production via the ERK/JNK pathway and accelerates renal fibrosis by TGF-β1/SMAD2/3 signaling [282].

In addition, as the main downstream enforcer of ER stress, C/EBPζ can regulate ER stress. A previous study showed that C/EBPζ upregulation in primary mouse embryo fibroblasts induced by tunicamycin can increase Gadd34 expression by binding to its promoter, which encodes the regulatory subunit of an eIF2α-specific phosphatase complex that promotes global proteins biosynthesis [287]. Accelerated protein biosynthesis results in unfolded and misfolded proteins that cause ER stress under pathophysiological conditions to promote fibrosis. This positive feedback between C/EBPζ and ER stress may occur in various tissues under persistent pathological irritation to promote the progression of injuries or diseases.

These exerting evidence shows that C/EBPζ upregulation can promote renal fibrosis through various mechanisms. However, these studies were carried out in kidney tissue rather than cells. Considering that C/EBPζ is ubiquitously expressed [31] and can be detected in renal parenchymal cells such as podocytes and inflammatory/immune cells such as macrophages [288, 289], further research is required to investigate the roles of C/EBPζ of different renal cell types in kidney fibrosis.

3.4. C/EBPs in Heart Fibrosis

Heart fibrosis is a common pathophysiological manifestation of most cardiovascular diseases that are the leading cause of death around the world [112]. Cardiac fibrosis is commonly categorized two types: reactive interstitial fibrosis and replacement fibrosis [2, 112]. Reactive interstitial fibrosis occurs in interstitial and perivascular spaces without significant cardiomyocyte loss and has similar fibrogenic responses to other tissues; replacement fibrosis occurs at the site of cardiomyocyte death and replaces with ECM and noncardiomyocyte to maintain heart integrity [2, 112]. In the heart, resident cardiac fibroblast differentiation into myofibroblasts is a key cellular process that drives the fibrotic response in many different conditions associated with heart failure [290, 291]. Cardiomyocytes are also critical contributors to the myocardial fibrotic response and can exhibit a fibrogenic program that can product ECM or lead to fibroblast activation under various pathophysiologic conditions [291, 292]. In addition, other cell types such as macrophages is implicated in fibrotic remodeling of the heart [183]. Here, we discuss the roles of C/EBPs in these cells during cardiac fibrosis (Figure 6).

3.4.1. C/EBPβ

C/EBPβ is detected in normal heart tissue under physiologic conditions; however, it can be downregulated in cardiomyocytes by endurance exercise, resulting in cardiomyocyte hypertrophy and proliferation without fibrosis [86]. Although C/EBPβ may be involved in the physiologic remolding of cardiomyocytes, the relationship between change in C/EBPβ protein level or activity and cardiac fibrosis under pathological conditions remains unclear. DCM can induce severe fibrosis and inhibit C/EBPβ expression in heart tissue [34, 293], while C/EBPβ overexpression can inhibit cardiac fibrosis caused by DCM [34]. In addition, enhanced cardiac fibrosis, decreased cardiac functions, and high heart C/EBPβ protein levels have been observed in models of experimental autoimmune myocarditis (EAM), spontaneously hypertensive rats, and transverse aortic constriction (TAC) [38, 86, 294]. Furthermore, C/EBPβ knockdown attenuates Col1al, Col3a1, and α-SMA expressions in the heart tissue of EAM rats [38], suggesting that C/EBPβ in various cell types may affect cardiac fibrosis in different ways during different disease states.

C/EBPβ exerts different effects on cardiac fibroblasts under various pathological stimuli. Some studies have reported a negative correlation between C/EBPβ levels in cardiac fibroblasts and cardiac fibrosis. For instance, C/EBPβ expression is downregulated in the cardiac fibroblasts with high Col1al, Col3a1, and TGF-β1 expression induced by high glucose, whereas C/EBPβ overexpression in activated cardiac fibroblasts significantly attenuates ECM deposition in vitro [34]. Furthermore, C/EBPβ binds to the angiotensin-converting enzyme 2 (Ace2) promoter and activates its expression, which catalyzes angiotensin II (Ang II) cleavage into Ang (1-7) [34, 295]. Ang II then binds to the angiotensin II type I receptor (AT1R) on the surface of fibroblasts, leading to ECM expression and secretion in various ways [296], whereas Ang (1-7) alleviates cardiac fibrosis and heart dysfunction by binding to and activating its receptor (MasR), thereby downregulating AT1R, AT2R, and ACE [34, 297]. However, other reports have shown that C/EBPβ is involved in the activation of cardiac fibroblasts. As an important fibrogenic factor, TGF-β1 can induce C/EBPβ protein expression of in cardiac fibroblasts; however, lentivirus-mediated C/EBPβ silencing can inhibit the upregulation of inflammatory factors and cytoskeletal proteins and the differentiation of cardiac fibroblasts caused by TGF-β1 [38]. Furthermore, Tgf-b1 is positively regulated by C/EBPβ in cardiac fibroblasts [298], forming a positive feedback loop that may play an important role in the activation of cardiac fibroblasts. In addition, norepinephrine can induce C/EBPβ, IL-6, and IL-6R expressions in nonmyocytes (predominantly of cardiac fibroblasts), with Cebpb mRNA levels elevating earlier than Il-6 and Il-6r mRNA levels in vivo [299]. C/EBPβ, also known as nuclear factor for IL-6 expression (NF-IL6), can bind to the Il-6 promoter and upregulate its expression [300], indicating that C/EBPβ can upregulate IL-6 expression in cardiac fibroblasts. Autocrine or paracrine IL-6 binds to its receptor IL-6R on the surface of cardiac fibroblasts, leading to ECM expression and deposition via the MAPK and CaMKII-STAT3 pathways [288].

Although C/EBPβ has been reported to regulate cardiac fibrosis in cardiomyocytes, but its role is paradoxical. Recently, it has reported that C/EBPβ overexpression can attenuate high glucose-induced cardiomyocytes apoptosis by upregulating ACE2 expression, which alleviates cardiac fibroblast activity and ECM production [34]. Compared to p38α-knockout cardiomyocytes, the DNA binding activity of C/EBPβ to the Col1α1 promoter is enhanced in wild-type cardiomyocytes, inhibiting Col1α1 transcription [301]. These studies suggest that C/EBPβ negatively regulates cardiac fibrosis in cardiomyocytes; however, C/EBPβ overexpression in primary cardiomyocytes has been reported to inhibit peroxisome proliferator-activated receptor γ coactivator-1 alpha (Pgc1a) mRNA and protein levels in fibrotic heart tissue from spontaneously hypertensive rats [86, 294], indicating that C/EBPβ can negatively regulate PGC-1α expression. PGC-1α is an important coactivator that regulates mitochondrial biogenesis and function in various organs and tissues [302]. PGC-1α upregulation in cardiomyocytes reduces TAC-induced heart fibrosis by inhibiting the mitochondrial unfolding protein response [303]. In addition, C/EBPβ can directly increase IL-6 production in cardiacmyocytes [299]. IL-6 not only binds to IL-6R on the surface of cardiomyocytes and induces myocardial hypertrophy via the MAPK and CaMKII-STAT3 pathways but also binds to IL-6R on the surface of cardiac fibroblasts and activates them [299]. Thus, C/EBPβ appears to positively regulate cardiac fibrosis in cardiomyocytes.

In brief, the relative contribution of C/EBPβ various cell types in heart fibrosis may be dependent on the underlying cause of cardiac injury and different expression of its isoforms.

3.4.2. C/EBPδ

Mice lacking C/EBPδ are viable and healthy and exhibit no abnormalities, indicating that C/EBPδ is not vital for survival [53, 97]. In most cells including cardiomyocytes, C/EBPδ expression is low under normal physiological conditions but can be rapidly induced by external stimuli [31]. Since C/EBPδ plays physiological roles in cell differentiation, proliferation, apoptosis, energy metabolism, and inflammation by regulating the expression of specific genes [31, 42], it may affect the pathogenesis of diseases such as cardiac fibrosis.

C/EBPδ expression is upregulated in the heart by adverse stimuli such as hypertension, LPS, and norepinephrine, similar to the liver [299, 304, 305]. Studies of cardiac fibrosis have mainly focus on the role of C/EBPδ in cardiomyocytes. For instance, enhanced C/EBPδ transcriptional activity in cardiomyocytes from Rad knockout mice under TAC has been shown to activate CTGF expression, which stimulates cardiac fibroblasts to produce more ECM [306]. In addition, C/EBPδ protein levels can be induced by IL-6 and mediated by STAT3 in cardiomyocytes, leading to cardiac hypertrophy which can cause cardiac fibrosis through multiple mechanisms [299, 307]. These results support the conclusion that C/EBPδ positively regulates the occurrence and development of cardiac fibrosis.

3.4.3. C/EBPζ

An extensive body of literature has shown that C/EBPζ is involved in cardiomyocyte apoptosis, cardiac hypertrophy, and heart fibrosis. Various stimuli such as TAC, myocardial infraction (MI), and diabetes activate ER stress by increasing C/EBPζ expression in myocardial fibrosis [308310]. In addition, C/EBPζ knockout mice display decreased cardiomyocyte apoptosis and subdued cardiac fibrosis under TAC, ischemia-reperfusion (I/R) injury, and Ang II-induced hypertension compared to wild-type mice [311313]. Thus, C/EBPζ may positively regulate cardiac fibrogenesis. Mechanistically, the upregulation of C/EBPζ by multiple factors, including phenylephrine, doxorubicin, and high glucose, has been reported to induce cardiomyocyte apoptosis [308, 314, 315], which can lead to organ remodeling and fibrosis after insult by activating fibroblasts [21].

The role of C/EBPζ in noncardiomyocytes in fibrosis remains somewhat contradictory. Consistent with its role in cardiomyocytes, C/EBPζ upregulation by I/R or tunicamycin can cause apoptosis of cardiac fibroblasts, thereby mitigating fibrosis [316]. However, increased C/EBPζ levels in primary cardiac fibroblasts explored to Ang II can increase the expression of ECM proteins, as confirmed by a decrease in C/EBPζ expression and fibrotic markers after treatment with an ER stress inhibitor [317]. In cardiac macrophages, C/EBPζ upregulation by hypoxia-induced mitogenic factor under MI or C/EBPζ overexpression can increase STAT1 and STAT3 phosphorylation, which can promote macrophage M1 polarization and increase production of proinflammatory cytokines that reduce the viability and activation of cardiac fibroblast [318]. These studies indicate that C/EBPζ expression in noncardiomyocyte cells may contribute to cardiac fibrosis in different ways under diverse stimuli.

3.5. C/EBPs in Neural Fibrosis

Central nervous system (CNS) trauma generates cellular debris, activates resident cells, infiltrates circulating immune cells, and eventually forms two distinct scars: glial scar and fibrotic scar [319, 320]. As a unique form in CNS, glial scar is mainly formed by the accumulation of reactive astrocytes in injured sites [320]. Reactive astrocytes, characterized by the increased expression of glial fibrillary acidic protein, surround the lesion and separate the injured area from normal tissue [320, 321]. Fibrotic scar, located in the injured core, is characterized by the presence of fibroblasts and ECM deposition [320]. Although the similar of CNS fibrotic scar to other organ fibrosis, its formation process may be quite different due to the unique CNS environment [320]. Various cell types in CNS such as fibroblasts, astrocytes, microglia, pericytes, and endothelial cells play important roles in formation of fibrotic scar [320]. C/EBPδ is detected in astrocytes, microglia, and pericytes and has a crucial role in CNS function [31]. ECM deposition and C/EBPδ levels are observed in the spinal cord of patients with amyotrophic lateral sclerosis (ALS) and the brains of patients with Alzheimer’s disease, indicating that C/EBPδ is involved in neurological fibrosis [322, 323]. Here, we discuss the roles of C/EBPδ in astrocyte, microglia, and brain pericyte in CNS fibrosis (Figure 7).

Astrocytes are a highly abundant cell type in the CNS, with astrocytes to neurons ratio of 1 : 3 in the cortex of mice and rats and 1.4 : 1 in the human cortex [324]. Astrocytes maintain CNS homeostasis under physiological conditions and are activated by CNS injury and diseases [325]. Reactive astrocytes (activated) are a major source of chondroitin sulfate proteoglycans, a family of ECM proteoglycans, and can therefore contribute toward scar tissue by increasing ECM protein deposition [326, 327]. C/EBPδ-deficient mice display reduced glial scar formation after moderate spinal cord contusion injury at the mid-thoracic level, indicating that C/EBPδ promotes glial scar formation [328]. Furthermore, C/EBPδ expression is increased in astrocytes stimulated with factors such as IL-1β, IL-6, TNF-α, or prostaglandin E2 [322, 328, 329]. High C/EBPδ levels can directly upregulate the expression of MMP3, which promotes the migration of inactive astrocytes to the injured area, resulting in glial scar formation [328]. However, C/EBPδ can also bind to the miR-153a promoter and upregulate its expression to repress the transcription of thrombospondin 1 (TSP1) via its 3UTR [191, 329]. In addition, C/EBPδ directly upregulate Complement 3 (C3) expression in astrocytes [330]. Besides, C/EBPδ knockout mice display a complete loss of nerve growth factor (NGF) induction in the cerebral cortex under β2-adrenergic receptor agonist treatment, with in vitro experiments confirming that NGF is a direct downstream target gene of C/EBPδ [331]. Although TSP1, C3, and NGF play an important role in fibrotic diseases, such as renal fibrosis and cardiac fibrosis [332334], further research is required to determine whether these factors mediate the regulation of astrocyte C/EBPδ in CNS fibrosis.

Pericytes are distributed throughout the body but have a higher density in the CNS [335]. Pericytes expressing the fibroblast markers α-SMA, fibronectin, and prolyl-4-hydroxylase (P4H) can give rise to fibroblast-like cells (type A pericytes) that constitute the fibrotic compartment of scars and are required for fibrosis and ECM deposition [336, 337]. C/EBPδ can be detected in brain pericytes and induced by IL-1β in a concentration- and time-dependent manner [258, 338]. In addition, pericytes with high C/EBPδ levels possess lower α-SMA, fibronectin, and P4H expression, indicating that C/EBPδ can negative regulate the differentiation of pericytes into fibroblasts.

Macrophages in the brain, also known as microglia, are critical for orchestrating the injury response in the CNS [339]. Nuclear C/EBPδ levels are increased in microglia from ALS patients and G93A-SOD1 mice (animal model of ALS), indicating that microglial C/EBPδ may promote fibrosis in CNS [323, 340]. However, the detailed mechanisms through which C/EBPδ regulates fibrosis in microglia require further study.

Available reports have shown that C/EBPδ upregulation exerts profibrotic or antifibrotic effect in CNS fibrosis depending on different cell types, but the clear and definite mechanisms are unclear. Next studies could be required to uncover the roles of C/EBPδ in neural fibrosis through Cebpd gene-modified animal models in specific CNS cells.

3.6. C/EBPs in Fibrosis of Other Tissues
3.6.1. Muscle Fibrosis

As an essential component of skeletal muscle, ECM provides a framework structure that holds myofibers, blood capillaries, and nerves to support the force transmission, maintenance, and repair of muscle fibers [341]. Skeletal muscle fibrosis often occurs after major muscle trauma or extensive surgical reconstructions and also is a hallmark of muscular dystrophies and aging [341, 342]. Fibrosis of skeletal muscle can impair muscle function, inhibit muscle regeneration after injury, and increase muscle susceptibility to reinjury [341, 343]. The predominant cell type responsible for ECM deposition in muscle fibrosis is fibroblast [343]. In addition, several signaling pathways have been reported to play an important roles in promoting muscle fibrosis, including TGF-β1, CTGF, Myostatin, Wnt, PDGF, and vascular endothelial growth factor (VEGF) [341, 343]. C/EBPα and C/EBPδ can be detected in muscle tissue and play an important role in fibrosis of skeletal muscle [282, 286]. Here, we discuss the relationship and roles of C/EBPα and C/EBPδ in skeletal muscle fibrosis (Figure 8).

C/EBPα can be detected in skeletal muscle tissue, indicating that it may affect muscle fibrosis [344, 345]. In a full-thickness supraspinatus tear rat model, simvastatin was reported to reduce Cebpa gene expression, decrease the mRNA levels of ECM synthesis-, fibrosis-, and fibroblast proliferation-related genes, and inhibit collagen accumulation by 50% in muscles [346], indicating that C/EBPα plays a significant role in muscle fibrosis. In addition, unloading conditions were found to decrease the fibroprogenitor markers’ expression and C/EBPα mRNA levels in a glycerol model of muscle regeneration [347], further suggesting that C/EBPα expression correlates negatively with muscle fibrosis. In addition, C/EBPδ is detected in muscle tissue and induced by activated STAT3 during catabolic conditions, such as chronic kidney disease and cancer cachexia [348, 349]. C/EBPδ directly upregulates Myostatin expression by binding to its promoter, which activates the SMAD2/3/AKT pathway and causes muscle wasting [348, 349]. In addition, elevated C/EBPδ increases Atrogin-1 and MuRF-1 levels, triggering the ubiquitin-proteasome system to accelerate muscle wasting and fibrotic deposition [349, 350]. These studies indicate that C/EBPα has an antifibrotic effect in skeletal muscle fibrosis, while C/EBPδ promotes the fibrosis of skeletal muscle under different stimuli.

3.6.2. Adipose Tissue Fibrosis

Adipose tissue is a complex heterogeneous tissue composed of adipocytes and nonadipocytes. Excess lipids and adipocyte hypertrophy can lead to hypoxia and inflammation in fat tissue during obesity [351]. Adipose tissue hypertrophy causes hypoxia to induce HIF-1α expression, upregulating many extracellular factors such as collagens that establish and remodel ECM. [352]. In cellular level, fibroblasts and inflammatory cells such as lymphocytes, mast cells, and macrophages play vital roles in producing depot-specific ECM and adipose tissue fibrosis [351]. C/EBPα and C/EBPβ play an important role in maintaining adipose tissue homeostasis and also participate in fibrosis of adipose tissue (Figure 8).

Collagen accumulation is increased in the adipose tissue of patients with HIV-1-related lipoatrophy, whereas C/EBPα expression is reduced [353]. In addition, cancer cachexia can lead to the loss of adipose tissue and increased fibrosis in the tissue matrix, accompanied by a significant decrease in C/EBPα mRNA and protein expression [354]. Besides, high-dose G-CSF also causes severe fibrosis and downregulates C/EBPα expression in fat grafts [355]. These studies indicate that C/EBPα negatively correlates with adipose fibrosis caused by different diseases or stimuli. Besides, as a regulator of the adipogenic/lipogenic transcription, C/EBPβ overexpression promotes the differentiation of preadipocytes into adipocytes, causing adipocyte hypertrophy [356]. Adipose tissue hypoxia is induced by adipocyte hypertrophy and hyperplasia, resulting in inflammation and fibrosis [357], indicating that C/EBPβ positively correlates with adipose fibrosis. Further studies may be required to explore the detailed role of C/EBPα and C/EBPβ in adipocytes and nonadipocytes during adipose tissue fibrosis and whether other C/EBPs affect the fibrosis process of adipose tissue.

3.6.3. Skin Fibrosis

Like other organ fibrosis, skin fibrosis is the excessive ECM deposition in the dermis and occurs following tissue injury such as burns, trauma, infection, surgery, and radiation, leading to scars that limit movement and cause significant psychological distress for patients [13, 358]. Many molecular pathways have been implicated in the development of skin fibrosis, including TGF-β, Wnt, and epidermal growth factor receptor (EGFR) signaling pathways [359]. Furthermore, myofibroblasts derived from dermal fibroblasts, pericytes, dermal adipocytes, and perivascular cells play a vital role in skin fibrosis [13, 360]. In addition, multiple cell types in skin such as keratinocytes, T cells, and macrophages have been implicated in skin fibrosis [13]. Recent studies have shown that C/EBPβ and C/EBPγ participated in skin fibrosis through different mechanisms [249, 250] (Figure 8).

In dermal fibroblasts, Col1α1 and Col1α2 are target genes of C/EBPβ and increased C/EBPβ expression induced by inflammatory factors, such as interferon beta (IFN-β) and IFN-γ, inhibits not only Col1α1 and Col1α2 expression but also the levels of Col3α1 and fibronectin, which suppresses ECM deposition [210, 211, 361]. In addition, a recent report showed that C/EBPγ can promote skin wound healing, indicating that C/EBPγ may play an important role in fibroblast activation. Wounding induces C/EBPγ expression in keratinocytes, while inhibiting C/EBPγ using siRNA can impair wound healing in vivo and in vitro [362]. C/EBPγ silencing also inhibits the migration of keratinocytes induced by EGF or serum, whereas C/EBPγ overexpression enhances their migration to EGF or serum via regulating the phosphorylation of EGFR, which affects cell migration and epidermal wound healing [362]. There is strong evidence that keratinocytes activate fibroblasts and cause them to produce growth factors, which in turn increases keratinocyte proliferation [363]. Activated fibroblasts are critical in creating ECM structures that support the other cells involved in effective wound healing [364].

These studies only detect C/EBP levels of mRNA and protein expression at the tissue level, not the cell level, raising several questions: (1) Is the decrease in C/EBPs and increase of tissues fibrosis a concomitant or causal relationship? (2) Does the transcriptional activity of C/EBPs change when C/EBPs protein levels decrease? (3) What are the roles of C/EBPs in the various cell types found in muscle, fat, and skin during fibrosis? More in-depth research is needed in the future to answer these questions.

In summary, C/EBPs can exert different effects on fibrosis in the same organ or tissue fibrosis. Some C/EBPs inhibit fibrosis in various organs; for instance, C/EBPα expression is decreased in several types of organ fibrosis, except in renal fibrosis, and C/EBPα overexpression lessens fibrosis, indicating the antifibrotic effect of C/EBPα under most conditions. Conversely, some C/EBPs accelerate fibrosis in various organs. For example, C/EBPδ expression and activity are increased in different types of nonliver fibrosis, with C/EBPδ deficiency inhibiting fibrosis, suggesting C/EBPδ has profibrotic effects under most conditions. Other C/EBPs, such as C/EBPβ, can have positive or negative effects on fibrosis depending on the cell type and stimulus. The overall effects of C/EBPs on fibrosis in different organs are summarized in Table 1.


Hepatic fibrosisPulmonary fibrosisRenal fibrosisCardiac fibrosisFibrosis of CNSMuscle fibrosisAdipose fibrosisSkin fibrosis

C/EBPα--+/---
C/EBPβ+/-+-+/-+-
C/EBPγ-+
C/EBPδ-+++++
C/EBPζ+/-+/-++

“+” means positive effect; “-” means negative effect; “+/-” means that the effects are not consistent.

4. Crosstalk between C/EBPs and Classical Fibrotic Factors

Studies in recent decades have shown that some conserved fibrotic molecules or classical fibrotic factors drive fibrogenesis in different organs and species. These classical fibrotic factors involve TGF-β1, CTGF, and PDGF [1, 2, 14]. The crosstalk between C/EBPs and classical fibrotic factors may play the important role in C/EBPs’ regulation of fibrosis. Existing reports focus on the role of crosstalk between C/EBPs and TGF-β1 or CTGF in fibrosis, in which we discuss these relations below.

4.1. C/EBPs Crosstalk with TGF-β1

TGF-β has been well-documented as a profibrotic cytokine since its first reported role in stimulating the expression of ECM in fibroblasts [365]. Three separate TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3) have been identified in mammals. These TGF-β isoforms share a similar biologically active region and can bind to TGF-β receptor 2 (TGFR2), which recruits and activates TGFR1 to activate receptor signaling [15]. In human, TGF-β1 was found to be the most abundant isoform and is widely expressed by most cells [366]. TGF-β signal acts on various cell types to drive fibrosis through both the SMAD- and non-SMAD-mediated pathways. In addition to tissue fibrosis, TGF-β1 also regulates many biological responses, such as cell proliferation, differentiation, autophagy, and immune response [15].

C/EBPs exhibit diverse regulatory relationships with TGF-β1 during fibrosis in different organs and can both up- and downregulate TGF-β1 activity or expression in different cell types. For example, C/EBPα can upregulate Leptin expression, which enhances the TGF-β1 signaling in normal rat kidney fibroblasts [260, 261]. Meanwhile, C/EBPβ directly increases TGF-β1 expression in cardiac fibroblasts and pulmonary macrophages and can bind to the Tfg-b1 promoter and suppress its expression in HSCs [42, 103, 298]. C/EBPζ also upregulates TGF-β1 expression through the HMGB1/TLR4/NF-κB/IL-1β pathway in renal tissue [282].

TGF-β1 can also indirectly modulate the expression or activity of C/EBPs. For example, TGF-β1 not only upregulates C/EBPβ expression in lung fibroblasts and HSCs but also enhances C/EBPβ activity by promoting its acetylation in alveolar epithelial cells [149, 152, 203, 213]. In tubular epithelial cells, TGF-β1 suppresses C/EBPβ expression through the PDE/cAMP/Epac pathway to regulate mitochondria biogenesis [267], yet in cardiac fibroblasts, TGF-β1 treatment inhibits C/EBPζ expression [316]. Furthermore, the positive feedback loop formed by TGF-β1 and C/EBPβ in cardiac fibroblasts and by TGF-β1 and C/EBPδ in pancreatic stellate cells may accelerate their activation [298, 367]. These research indicates that the crosstalk between C/EBPs and TGF-β1 plays an important role in regulation of fibrosis by C/EBPs. The regulatory mechanisms involving C/EBP and TGF-β1 are summarized in Table 2.


OrganEffectReferences

C/EBPs positively regulate TGF-β1 activity or expression
KidneyC/EBPα directly upregulated the leptin expression, which enhances the TGF-β signaling in normal rat kidney fibroblasts[260, 261]
HeartC/EBPβ can upregulate target gene Tgf-b1 in the cardiac fibroblasts[298]
KidneyOverexpression C/EBPβ polarizes macrophages to M2, which has increased levels of TGF-β1[189, 264]
PancreasC/EBPδ upregulates TGF-β1 expression in pancreatic stellate cells[367]
LungC/EBPζ deficiency repressed the M2 polarization, which then attenuated TGF-β1 secretion in macrophages[254]
KidneyC/EBPζ upregulates the expression of TGF-β1 through the HMGB1/TLR4/NF-κB/IL-1β pathway in renal tissue[282]
C/EBPs negatively regulate TGF-β1 activity or expression
LiverC/EBPβ binds to the promoter of TGF-β1 and suppresses its expression in HSCs[103]
TGF-β1 positively regulate C/EBP expression or activity
LiverTGF-β1 increases the expression or activity of C/EBPβ to promote the expression of collagens in HSCs[149, 152]
LungTGF-β1 can upregulate the protein level of C/EBPβ in the lung fibroblasts[203]
LungTGF-β1 enhances the activity of C/EBPβ through increasing its acetylation to induce the EMT of alveolar epithelial cells[213]
PancreasTGF-β1 increases the expression of C/EBPδ in pancreatic stellate cells[367]
TGF-β1 negatively or not regulate C/EBP expression or activity
LungTGF-β1 treatment did not affect the expression of C/EBPα in lung fibroblast[43]
LungTGF-β1 inhibits the expression of C/EBPβ in alveolar epithelial cells[383]
KidneyTGF-β1 suppresses the expression of C/EBPβ through the PDE/cAMP/Epac pathway to regulate mitochondria biogenesis in tubular epithelial cells[267]
HeartTGF-β1 inhibits the expression of C/EBPζ to suppress the apoptosis of cardiac fibroblasts[316]

4.2. C/EBPs Crosstalk with CTGF

CTGF (also known as cellular communication network factor 2 (CCN2)) is one of the best-studied members of the CCN family, which is involved in regulating a variety of important biological functions and pathological processes including tissue fibrosis [17]. CTGF was firstly discovered in fibroblasts and endothelial cells and has since been detected in many organs and tissues [368]. In addition to participating in many biological functions, including cell proliferation, differentiation, and adhesion, CTGF drives the onset and progression of fibrosis in many organs and tissues through various mechanisms [17, 368]. CTGF has been consistently associated with fibrotic remodeling in various organs and has been widely used as the marker to detect fibrosis.

As a downstream modulator of TGF-β1, CTGF has been implicated in the occurrence and development of fibrosis [17, 369]. Multiple recent studies have examined direct and indirect mechanisms of regulation between C/EBPs and CTGF. For instance, C/EBPβ has been shown to indirectly upregulate CTGF expression in lung fibroblasts and directly enhance its expression in human alveolar epithelial cells [204, 212]. Moreover, C/EBPδ directly increases CTGF expression in cardiomyocytes [306]. However, C/EBPα can indirectly suppress CTGF expression in lung fibroblasts and renal podocytes [36, 43]. These studies suggest that CTGF is involved in the regulation of fibrosis by C/EBPs. The regulatory mechanisms involving C/EBPs and CTGF are summarized in Table 3.


OrganEffectReferences

C/EBPs positively regulate CTGF activity or expression
LungC/EBPβ upregulates the expression of CTGF in lung fibroblasts through ADAM17[204]
LungC/EBPβ enhances CTGF expression in human alveolar epithelial cells[212]
HeartC/EBPδ can increase CTGF expression in cardiomyocytes[306]
C/EBPs negatively regulate CTGF activity or expression
LungOverexpression of C/EBPα inhibited the mRNA level of CTGF in lung fibroblasts vice versa[43]
KidneyOverexpression C/EBPα reduced the increased mRNA level of CTGF in podocytes induced by adriamycin[36]

5. Therapy Strategies Targeting C/EBPs in Fibrosis

Given that C/EBPs play important roles in the pathogenesis of fibrosis, regulating their expression or activity is an attractive strategy for treating fibrotic diseases. Various in vivo experiments have shown that C/EBPα overexpression can inhibit CCl4-induced liver fibrosis [37], C/EBPβ deficiency in hematopoietic cells can mitigate bleomycin-induced pulmonary fibrosis [190], C/EBPδ lost can aggravate UUO-induced renal fibrosis [26], and C/EBPζ deficiency can alleviate TAC-induced cardiac fibrosis [311], thus providing an experimental basis for the realization of this strategy. Here, we have reviewed interventions involving C/EBPs that improve fibrotic diseases, which have been divided into four categories: oligodeoxynucleotides, oligopeptides, clinical medicines, and compounds (Table 4).


CategoriesCompoundC/EBPsDiseasesEffectReferences

OligodeoxynucleotidesC/EBPα-saRNAC/EBPαHepatocellular carcinomaIt upregulates C/EBPα protein in hepatocytes to inhibit cancer[126]
C/EBPβ-dODNC/EBPβHepatic fibrosisC/EBPβ-dODN inhibits the activation of C/EBPβ and increases the activation of HSCs[103]

OligopeptidesDominant negative C/EBPC/EBPα, C/EBPβ, C/EBPδ, C/EBPεCardiac fibrosisIt inhibits the activations of C/EBPα, C/EBPβ, C/EBPδ, and C/EBPε and improves the cardiac fibrosis[106]
C/EBPα-DNC/EBPαErythropoietic dysplasiaC/EBPα-DN suppresses the activation of C/EBPα in hematopoietic stem/progenitor cells[384]
A-C/EBPC/EBPβRelated fat fibrosisA-C/EBP inhibits the activation of C/EBPβ in preadipocytes[373]

Clinical medicinesSimvastatinC/EBPαMuscle fibrosisSimvastatin inhibits the expression of C/EBPα protein and improves the muscle fibrosis[346]
AtorvastatinC/EBPβCardiac fibrosisAtorvastatin inhibits the expression of C/EBPβ protein and improves the cardiac fibrosis[294]
Adefovir dipivoxilC/EBPβHepatic fibrosisAdefovir dipivoxil inhibits the expression of C/EBPβ protein and improving the hepatic fibrosis[148]
Cortisol and dexamethasoneC/EBPβ, C/EBPδRelated lung fibrosisCortisol and dexamethasone enhance the activation of C/EBPβ and C/EBPδ in the lung epithelial cells[238]
MevastatinC/EBPδLiver cancerMevastatin inhibits the expression of C/EBPδ protein in hepatoma cells[164]
ClenbuterolC/EBPδGliomaClenbuterol increases the expression of C/EBPδ in glioma cells[331]
AtorvastatinC/EBPζCardiac fibrosisAtorvastatin inhibits the expression of C/EBPζ and inhibiting the cardiac fibrosis[385]
GeranylgeranylacetoneC/EBPζHepatic fibrosisGeranylgeranylacetone increases the expression of C/EBPζ in HSCs and inhibiting the hepatic fibrosis[386]
DeferasiroxC/EBPζHepatic fibrosisDeferasirox inhibits the expression of C/EBPζ and inhibiting the hepatic fibrosis[387]
CandesartanC/EBPζRenal fibrosisCandesartan inhibits the expression of C/EBPζ and inhibiting the renal fibrosis[281]
TelmisartanC/EBPζCardiac fibrosisTelmisartan inhibits the expression of C/EBPζ and inhibiting the cardiac fibrosis[388]
MetforminC/EBPζIntrauterine adhesionMetformin inhibits the expression of C/EBPζ and the intrauterine adhesion[107]

CompoundsBaicalinC/EBPα, C/EBPβ, C/EBPγ, C/EBPδ, C/EBPζFat fibrosisBaicalin inhibits the expression of C/EBPα protein and increases the expressions of C/EBPβ, C/EBPγ, C/EBPδ, and C/EBPζ[389]
5-Aza-dCC/EBPα, C/EBPβ, C/EBPγHepatic fibrosis5-Aza-dC inhibits the expressions of C/EBPα, C/EBPβ, and C/EBPγ[390]
LPSC/EBPα, C/EBPδHepatic fibrosisLPS increases the expressions of C/EBPα and C/EBPδ and inhibits the hepatic fibrosis[28]
CurcuminC/EBPαHepatic fibrosisCurcumin upregulates the expression of C/EBPα protein and inhibits the activation of HSCs[374]
PeretinoinC/EBPαHepatic fibrosisPeretinoin upregulates the expression of C/EBPα in hepatocytes and alleviates hepatic fibrosis[128]
Vitamin AC/EBPαHepatic fibrosisVitamin A upregulates the expression of C/EBPα protein and inhibits the activation of HSCs[117]
Vitamin EC/EBPαHepatic fibrosisVitamin E upregulates the expression of C/EBPα in hepatocytes and inhibits hepatic fibrosis[136]
Epigallocatechin-3-gallateC/EBPαHepatic fibrosisVitamin E upregulates the expression of C/EBPα in hepatocytes and inhibits hepatic fibrosis[115]
Trichostatin AC/EBPαHepatic fibrosisTrichostatin A upregulates the expression of C/EBPα protein and inhibits the activation of HSCs[122]
BIX-01294C/EBPαLung fibrosisBIX-01294 upregulates the expression of C/EBPα protein and inhibits the activation of lung fibroblasts[43]
EchinomycinC/EBPβFat fibrosisEchinomycin inhibits the expression of C/EBPβ protein and the adipogenesis[356]
Tanshinone IIA and PuerarinC/EBPβCardiac fibrosisTanshinone IIA and Puerarin inhibit the expression of C/EBPβ protein in macrophages and inhibit the cardiac fibrosis[391]
N-acetyl-Leu-Leu-norleucinalC/EBPβLung fibrosisN-acetyl-Leu-Leu-norleucinal blocks the activation of C/EBPβ and inhibits the lung fibrosis[392]
OltiprazC/EBPβHepatic fibrosisOltipraz increases the activation of C/EBPβ and inhibits the hepatic fibrosis[103]
ArmepavineC/EBPβHepatic fibrosisArmepavine inhibits the activation of C/EBPβ and inhibits the hepatic fibrosis[393]
8-O-cAMPC/EBPβRenal fibrosis8-O-cAMP increases the expression and activation of C/EBPβ and inhibits the renal fibrosis[266]
ChrysinC/EBPδNeurological fibrosisChrysin inhibits the expression of C/EBPδ in microglial cells[394]
Ursolic acidC/EBPδRenal fibrosisUrsolic acid inhibits the expression of C/EBPδ protein and the kidney fibrosis[348]
ArtesunateC/EBPζIntra-articular adhesionArtesunate inhibits the expression of C/EBPζ and the intra-articular adhesion[395]
CurcuminC/EBPζLung fibrosisCurcumin inhibits the expression of C/EBPζ and the lung fibrosis[250]
MelatoninC/EBPζHepatic fibrosisMelatonin inhibits the expression of C/EBPζ protein and the hepatic fibrosis[396]
Tauroursodeoxycholic acidC/EBPζLung fibrosisTauroursodeoxycholic acid inhibits the expression of C/EBPζ and the lung fibrosis[169]
4-Phenylbutyric acidC/EBPζRenal fibrosis4-Phenylbutyric acid inhibits the expression of C/EBPζ and the renal fibrosis[283]
Ginsenoside Rg1C/EBPζRenal fibrosisGinsenoside Rg1 inhibits the expression of C/EBPζ and the renal fibrosis[397]
QuercetinC/EBPζRenal fibrosisQuercetin inhibits the expression of C/EBPζ and the renal fibrosis[286]
N-Acetyl-seryl-aspartyl-lysyl-prolineC/EBPζCardiac fibrosisN-Acetyl-seryl-aspartyl-lysyl-proline inhibits the expression of C/EBPζ and the cardiac fibrosis[309]
ApocyninC/EBPζCardiac fibrosisApocynin inhibits the expression of C/EBPζ and the cardiac fibrosis[398]
Execdin-4C/EBPζCardiac fibrosisExecdin-4 inhibits the expression of C/EBPζ and the cardiac fibrosis[399]
HomoharringtonineC/EBPζEpidural FibrosisHomoharringtonine increases the expression of C/EBPζ and inhibits the epidural fibrosis[400]

Oligodeoxynucleotides and oligopeptides specifically target C/EBPs at the RNA level and protein level. Recent reports have shown that short duplex RNA oligonucleotides can target the promoter regions of genes and mediate their transcriptional activation [126, 370, 371]. Short activating RNA (saRNA) are important RNA oligonucleotides that enhance gene expression through transcriptional and epigenetic alterations [372]. For example, C/EBPα-saRNA can increase C/EBPα RNA and protein levels in hepatocytes [126]. Since C/EBPα expression is mostly reduced in fibrotic diseases, the specific upregulation of C/EBPα may improve fibrotic diseases such as hepatic fibrosis. In addition, oligopeptides can bind to target proteins and inhibit their function. For instance, the dominant-negative C/EBP (A-C/EBP) protein expressed by an exogenously specific nucleotide sequence, which possesses a leucine zipper but lacks functional DNA-binding and transactivation domains and forms stable inactive heterodimers with C/EBPβ to inhibit its transcriptional activation in preadipocytes and adult epicardium, reduce injury-induced cardiac fibrosis, and improve heart function [106, 373]. However, in vivo studies of the precise mechanisms and specific delivery systems are required before these advances can be applied to under clinical conditions.

Marketed clinical medicines, such as lipid-lowering drugs, hypoglycemic agents, and antiviral drugs have been shown to improve fibrosis while modulating the expression or activation of C/EBPs at the animal or cellular levels [107, 148, 346]. Clinical trials are needed to verify their efficacy as clinical antifibrosis treatments, as well as in-depth studies of the precise antifibrotic mechanisms, including C/EBP regulation. In addition, various traditional Chinese medicine compounds and monomers, such as echinomycin, tauroursodeoxycholic acid, curcumin, and quercetin have been shown to alleviate fibrotic diseases by regulating C/EBP expression in vivo and in vitro [169, 286, 356, 374]. Given the complex structures and existing mechanisms reported for these substances, they are likely to regulate C/EBP expression indirectly; however, their antifibrotic effects and the precise mechanisms, including whether they modulate C/EBPs, require further study.

To date, only two drugs have been approved for antifibrotic therapy of IPF: nintedanib and pirfenidone [3]. Nintedanib is an intracellular inhibitor of tyrosine kinases that have been implicated in the pathogenesis of fibrosis [375]. Pirfenidone, initially developed as an anti-inflammatory substance due to its ability to reduce the accumulation of inflammatory cells and cytokines, has been chiefly characterized as an antifibrotic agent that attenuates fibroblast proliferation and differentiation into myofibroblast, as well as the synthesis and deposition of ECM proteins by inhibiting TGF-β and other fibrogenic growth factors [376]. Despite recent studies that have elucidated key mechanisms, the precise molecular activities of nintedanib and pirfenidone remain unclear [375, 376], and further research is required to determine whether C/EBPs are involved in the antifibrotic effects of these two drugs.

6. Conclusions and Perspectives

In this review, we have mainly summarized a broad range of recent advances on C/EBPs research in the context of fibrosis. These studies have partly revealed the crucial and complex roles of C/EBPs in fibrotic onset and progression in multiple organs. In summary, C/EBPα exerts a notable antifibrotic effect in the liver, lung, and kidney fibrosis diseases, while paradoxically promoting fibrosis in the liver of older patients. C/EBPβ possesses an antifibrotic effect in skin fibrosis, while having a positive correlation with fat fibrosis. C/EBPγ can inhibit the lung fibrosis while promoting the skin fibrosis. C/EBPδ possesses a profibrotic effect in the heart, lung, kidney, and muscle fibrosis diseases. C/EBPζ exerts a profibrotic effect in kidney fibrosis. Modulating C/EBP expression and/or activity can exert antifibrotic effects in multiple organs; therefore, novel C/EBPs-based therapeutic methods for treating fibrosis have attracted considerable attention.

Despite the encouraging progress in exploring the relationship between C/EBPs and fibrosis, many critical questions still remain unanswered, and more knowledge is needed before C/EBPs are utilized clinically for fibrosis treatment. Most available studies were carried out in animal models of fibrosis, rather than in clinical specimens from fibrosis-related diseases. Definitive clinical evidence on the relationship between C/EBPs and fibrosis is necessary in research targeting C/EBPs for treatment of fibrotic diseases. In the future, more work is needed to determine the changes of C/EBPs (including genetic polymorphisms, mRNAs, proteins, isoforms, and PTM of C/EBPs) in clinical fibrotic specimens from different organs or same organ in different fibrotic states to confirm the role of C/EBPs in fibrosis and the correlation between their changes and fibrotic degree.

Second, the mechanism of C/EBPs in regulating fibrosis requires more in-depth studies. (1) Although fibrosis was previously thought to be irreversible, there is now a growing body of evidence suggesting that fibrosis is reversible in fibrotic diseases under some circumstances. Regulating ECM degradation is an important mechanism under fibrogenesis [12], which can be targeted in novel therapeutic strategies. The most important enzymes which contribute to ECM degradation are MMPs [377]. Some studies have shown that C/EBPs can regulate the expression of MMPs. For instance, C/EBPα can induces the expression and secretion of MMP8/9 in neutrophils to mediate ECM degradation of the liver [24]. Considering that MMPs are produced by various cell types and an important role of ECM degradation in fibrosis [12, 377], additional research is needed to explore the roles of C/EBPs in regulating ECM degradation including MMPs during fibrosis. (2) Metabolic dysregulation is increasingly recognized as an important pathogenic process that underlies fibrosis in many organs [3]. Indeed, C/EBPs also paly vital roles in fibrosis caused by metabolic abnormalities. For instance, decreased C/EBPα activity inhibits high-fat diet-induced liver fibrosis [75], while overexpression of C/EBPβ suppresses diabetes-induced cardiac fibrosis [34]. However, increased C/EBPδ exacerbates muscle fibrosis in diabetes conditions [348]. These studies indicate that C/EBPs may be involved in metabolic dysregulation. Future investigations of the regulatory relationships between C/EBPs and metabolic homeostasis may expand our understanding of C/EBPs functions and provide further support for fibrosis therapy by targeting C/EBPs. (3) In addition to forming heterodimers between C/EBPs to regulate other’s transcriptional functions, they can also bind to the gene promoters to regulate the protein expressions of different members. For instance, the complex of C/EBPα and C/EBPβ binds the Cebpa promoter and active the expression of C/EBPα in the liver [73]. Besides, C/EBP members can be detected in the same cell type under fibrosis, such as C/EBPα, C/EBPβ, C/EBPγ, C/EBPδ, and C/EBPζ in alveolar epithelial cells [196, 212, 223, 225, 242]. These studies indicate that C/EBPs appear to play a coordinated and likely, partially redundant role in many cell types. However, the effects of these coordinated interactions and complementary roles among C/EBPs during fibrotic process remain largely unknown. Additional studies are needed to explore the roles of C/EBP coordination and complementation in various fibrosis-related cell types to clarify the unique and common roles of each member in fibrosis. (4) Growing evidence shows that the nontranscriptional functions of transcription factors also play the important roles in various physiological and pathological processes [378380]. As an important transcription factor family, some C/EBP isoforms can also interact with other proteins and perform non-transcriptional functions. For example, C/EBPδ can bind to FANCD2 and facilitate its nuclear import [66]. More investigations on this topic will not only deepen the understanding of C/EBPs’ functions but also clarify the significance of both the transcriptional and nontranscriptional functions of C/EBPs in fibrosis to provide support for subsequent development of antifibrotic drugs targeting these different functions.

Third, considering that C/EBPs are multifunctional transcriptional factors that play different roles among different cell types, more in-depth studies are required to explore how to properly modulate C/EBP expression or activity in certain cell types and at proper stages to maximize the beneficial effects of C/EBPs on fibrosis and avoid unnecessary adverse effects. Technological advances have provided evidence on possible approaches for controlling fibrotic diseases by targeting C/EBP proteins. Coronavirus disease 2019 (COVID-19) heightened interest in the use of mRNA as vaccine and drug [381, 382]. Similar to C/EBPα-saRNA or decoy double-stranded oligodeoxynucleotides of C/EBPβ (C/EBPβ-dODN), the mRNA of C/EBP family members, when specifically delivered to the tissue, upregulates the expression of specific members or inhibits their transcriptional activity to improve fibrotic disease outcomes [103, 126]. Further research is needed to design and screen mRNA fragments of the C/EBP family members and explore the methods, optimal dosing, timing of administration, and side effects of these therapies. Additionally, advances in drug delivery systems including modified peptide-, albumin-, nanoparticle-, aptamer-, hydrogel-, or antibody-based systems show promise for developing clinical fibrosis management strategies which target C/EBPs.

Fibrosis is a common outcome following organ injury and leads to organ malfunction and potentially death. The existing evidence summarized in this review strengthens the hypothesis that C/EBPs may be effective targets for fibrosis treatment and will serve as a reference for further research in this field.

Abbreviations

ACE2:Angiotensin-converting enzyme 2
ADAM17:A disintegrin and metalloproteinase 17
ALS:Amyotrophic lateral sclerosis
AT1R:Angiotensin II type I receptor
Atg16L1:Autophagy-related 16 like 1
bZIP:Basic leucine zipper
CCl4:Carbon tetrachloride
CCL:C-C chemokine ligand
CCSP:Clara cell secretory protein
C/EBPs:CCAAT/enhancer-binding proteins
CFLAR:Fas-associated via death domain-like apoptosis regulator
CHOP:C/EBP homologous protein
CNS:Central nervous system
CTGF:Connective tissue growth factor
DBD:DNA-binding domain
DCM:Diabetic cardiomyopathy
DRP:Death receptor pathway
EAM:Experimental autoimmune myocarditis
ECM:Extracellular matrix
EGF:Epidermal growth factor
EMT:Epithelial-mesenchymal transition
ER:Endoplasmic reticulum
FANCD2:Fanconi anemia group D2 protein
FGF2:Fibroblast growth factor 2
FSP-1:Fibroblast-specific protein 1
GADD153:Growth arrest and DNA damage-inducible protein 153
HAS2:Hyaluronan synthase 2
HDAC1:Histone deacetylase 1
HIF-1α:Hypoxia-inducible factor-1α
HSC:Hepatic stellate cell
IFN:Interferon
IPF:Idiopathic pulmonary fibrosis
I/R:Ischemia-reperfusion
KLF5:Krüppel-like factor 5
LAP:Liver activation protein
LIP:Liver inhibitory protein
LPS:Lipopolysaccharide
LR-MSCs:Lung resident mesenchymal stem cells
MCD:Methionine-choline-deficient
MCP-1:Monocyte chemoattractant protein-1
MMP:Matrix metalloproteinase
MMT:Macrophage-to-myofibroblast transition
MP:Mitochondrial pathway
NASH:Nonalcoholic steatohepatitis
NGF:Nerve growth factor
P4HA1:Prolyl-4-hydroxylase alpha polypeptide 1
PAI-1:Plasminogen activator inhibitor-1
PDGF:Platelet-derived growth factor
PGC-1α:Peroxisome proliferator-activated receptor γ coactivator-1 alpha
PPARγ:Peroxisome proliferator-activated receptor γ
PTMs:Posttranslational modifications
ROS:Reactive oxygen species
RSK:Ribosomal S6 kinase
saRNA:Short activating RNA
SCAR:Steatohepatitis-associated circRNA ATP5B regulator
SGD:Specific granule deficiency
SIAH2:Siah E3 ubiquitin protein ligase 2
SMAD:Mothers against decapentaplegic
SOCS3:Suppressor of cytokine signaling 3
SREBP1c:Sterol regulatory element-binding protein 1c
STAT3:Signal transducer and activator of transcription 3
SUMOylation:Small ubiquitin-like modifier modification
TAC:Transverse aortic constriction
TAD:Transcriptional activation domain
TECs:Tubular epithelial cells
TGF-β:Transforming growth factor-β
TNF-α:Tumor necrosis factor α
TREM1:Triggering receptor expressed on myeloid cells 1
TRIB1:Tribbles pseudokinase 1
uORF:Upstream open reading frame
UTR:Untranslated regions
UUO:Unilateral ureteral obstruction.

Disclosure

The funders had no role in the study design, data collection and analysis, manuscript preparation, or decision to publish.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

L.W. and J.G. wrote the manuscript with assistance from other coauthors. J.G. supervised and revised the manuscript. All authors commented on the manuscript.

Acknowledgments

We thank Dr. Tian Fan (School of Life Sciences, Guangzhou University) sincerely for reviewing our manuscript and the constructive comments. We also thank Ran Li (Guangzhou Blood Center) for his work for modification of Figures 1 and 2. Figures 37 were modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License. (https://creativecommons.org/licenses/by/3.0/). We apologize to researchers whose work could not be cited in this review because of space limitations. Research in the authors’ laboratory is financially supported by the Major basic and applied basic research projects of Guangdong Province of China (2019B030302005), the Natural Science Foundation of China (81830113), the National Key Research and Development Program of China (2018YFC1704200), the Basic and applied basic research project of Guangdong Province of China (2020A1515010155), and the “Innovation and Strengthening University Project” Subsidized Project of Guangdong Pharmaceutical University (2018KTSCX112).

Supplementary Materials

Table S1: the proteins interacted with C/EBPs and the functions. (Supplementary Materials)

References

  1. N. C. Henderson, F. Rieder, and T. A. Wynn, “Fibrosis: from mechanisms to medicines,” Nature, vol. 587, no. 7835, pp. 555–566, 2020. View at: Publisher Site | Google Scholar
  2. D. C. Rockey, P. D. Bell, and J. A. Hill, “Fibrosis--a common pathway to organ injury and failure,” New England Journal of Medicine., vol. 372, no. 12, pp. 1138–1149, 2015. View at: Publisher Site | Google Scholar
  3. X. Zhao, J. Y. Y. Kwan, K. Yip, P. P. Liu, and F. F. Liu, “Targeting metabolic dysregulation for fibrosis therapy,” Nature Reviews Drug Discovery, vol. 19, no. 1, pp. 57–75, 2020. View at: Publisher Site | Google Scholar
  4. M. Zhang and S. Zhang, “T cells in fibrosis and fibrotic diseases,” Frontiers in Immunology, vol. 11, p. 1142, 2020. View at: Publisher Site | Google Scholar
  5. P. M. Tang, D. J. Nikolic-Paterson, and H. Y. Lan, “Macrophages: versatile players in renal inflammation and fibrosis,” Nature Reviews Nephrolog, vol. 15, no. 3, pp. 144–158, 2019. View at: Publisher Site | Google Scholar
  6. O. S. Kotsiou, K. I. Gourgoulianis, and S. G. Zarogiannis, “IL-33/ST2 axis in organ fibrosis,” Frontiers in Immunology, vol. 9, p. 2432, 2018. View at: Publisher Site | Google Scholar
  7. J. H. W. Distler, A. H. Györfi, M. Ramanujam, M. L. Whitifeld, M. Königshoff, and R. Lafyatis, “Shared and distinct mechanisms of fibrosis,” Nature Reviews Rheumatology, vol. 15, no. 12, pp. 705–1730, 2019. View at: Publisher Site | Google Scholar
  8. M. J. Moeller, R. Kramann, T. Lammers et al., “New aspects of kidney fibrosis-from mechanisms of injury to modulation of disease,” Frontiers in Medicine (Lausanne), vol. 8, p. 814497, 2022. View at: Publisher Site | Google Scholar
  9. Z. G. Ma, Y. P. Yuan, H. M. Wu, X. Zhang, and Q. Z. Tang, “Cardiac fibrosis: new insights into the pathogenesis,” International Journal of Biological Sciences, vol. 14, no. 12, pp. 1645–1657, 2018. View at: Publisher Site | Google Scholar
  10. J. G. Travers, F. A. Kamal, J. Robbins, K. E. Yutzey, and B. C. Blaxall, “Cardiac fibrosis: the fibroblast awakens,” Circulation Research, vol. 118, no. 6, pp. 1021–1040, 2016. View at: Publisher Site | Google Scholar
  11. A. Stempien-Otero, D. H. Kim, and J. Davis, “Molecular networks underlying myofibroblast fate and fibrosis,” Journal of Molecular and Cellular Cardiology, vol. 97, pp. 153–161, 2016. View at: Publisher Site | Google Scholar
  12. J. I. Jun and L. F. Lau, “Resolution of organ fibrosis,” Journal of Clinical Investigation, vol. 128, no. 1, pp. 97–107, 2018. View at: Publisher Site | Google Scholar
  13. M. V. Plikus, X. Wang, S. Sinha et al., “Fibroblasts: origins, definitions, and functions in health and disease,” Cell, vol. 184, no. 15, pp. 3852–3872, 2021. View at: Publisher Site | Google Scholar
  14. R. Weiskirchen, S. Weiskirchen, and F. Tacke, “Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications,” Molecular Aspects of Medicine, vol. 65, pp. 2–15, 2019. View at: Publisher Site | Google Scholar
  15. X. M. Meng, D. J. Nikolic-Paterson, and H. Y. Lan, “TGF-β: the master regulator of fibrosis,” Nature Reviews Nephrology, vol. 12, no. 6, pp. 325–338, 2016. View at: Publisher Site | Google Scholar
  16. B. M. Klinkhammer, J. Floege, and P. Boor, “PDGF in organ fibrosis,” Molecular Aspects of Medicine, vol. 62, pp. 44–62, 2018. View at: Publisher Site | Google Scholar
  17. Y. Ramazani, N. Knops, M. A. Elmonem et al., “Connective tissue growth factor (CTGF) from basics to clinics,” Matrix Biology, vol. 68-69, pp. 44–66, 2018. View at: Publisher Site | Google Scholar
  18. L. Borthwick and F. Oakley, “Editorial overview: fibrosis,” Current Opinion in Pharmacology, vol. 49, pp. vi–vii, 2019. View at: Publisher Site | Google Scholar
  19. E. A. Williamson, I. K. Williamson, A. M. Chumakov, A. D. Friedman, and H. P. Koeffler, “CCAAT/enhancer binding protein epsilon: changes in function upon phosphorylation by p38 MAP kinase,” Blood, vol. 105, no. 10, pp. 3841–3847, 2005. View at: Publisher Site | Google Scholar
  20. J. Tsukada, Y. Yoshida, Y. Kominato, and P. E. Auron, “The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation,” Cytokine, vol. 54, no. 1, pp. 6–19, 2011. View at: Publisher Site | Google Scholar
  21. Y. Yang, L. Liu, I. Naik, Z. Braunstein, J. Zhong, and B. Ren, “Transcription factor C/EBP homologous protein in health and diseases,” Frontiers in Immunology, vol. 8, p. 1612, 2017. View at: Publisher Site | Google Scholar
  22. Z. Cao, R. M. Umek, and S. L. McKnight, “Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells,” Genes and Development, vol. 5, no. 9, pp. 1538–1552, 1991. View at: Publisher Site | Google Scholar
  23. C. Yan, X. Wang, J. Cao, M. Wu, and H. Gao, “CCAAT/enhancer-binding protein gamma is a critical regulator of IL-1beta-induced IL-6 production in alveolar epithelial cells,” Public Library of Science One, vol. 7, no. 4, p. 35492, 2012. View at: Google Scholar
  24. E. Saijou, Y. Enomoto, M. Matsuda et al., “Neutrophils alleviate fibrosis in the CCl4-induced mouse chronic liver injury model,” Hepatology Communications, vol. 2, no. 6, pp. 703–717, 2018. View at: Publisher Site | Google Scholar
  25. A. Ndoja, R. Reja, S. H. Lee et al., “Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia,” Cell, vol. 182, no. 5, pp. 1156–1169.e12, 2020. View at: Publisher Site | Google Scholar
  26. J. Duitman, K. S. Borensztajn, W. P. Pulskens, J. C. Leemans, S. Florquin, and C. A. Spek, “CCAAT-enhancer binding protein delta (C/EBP δ) attenuates tubular injury and tubulointerstitial fibrogenesis during chronic obstructive nephropathy,” Laboratory Investigation, vol. 94, no. 1, pp. 89–97, 2014. View at: Publisher Site | Google Scholar
  27. J. A. Lekstrom-Himes, “The role of C/EBP(epsilon) in the terminal stages of granulocyte differentiation,” Stem Cells, vol. 19, no. 2, pp. 125–133, 2001. View at: Publisher Site | Google Scholar
  28. A. Sharma, A. K. Verma, M. Kofron et al., “Lipopolysaccharide reverses hepatic stellate cell activation through modulation of cMyb, small mothers against decapentaplegic, and CCAAT/enhancer-binding protein C/EBP transcription factors,” Hepatology, vol. 72, no. 5, pp. 1800–1818, 2020. View at: Publisher Site | Google Scholar
  29. D. P. Ramji and P. Foka, “CCAAT/enhancer-binding proteins: structure, function and regulation,” Biochemical Journal, vol. 365, no. 3, pp. 561–575, 2002. View at: Publisher Site | Google Scholar
  30. A. D. Friedman, “C/EBPα in normal and malignant myelopoiesis,” International Journal of Hematology, vol. 101, no. 4, pp. 330–341, 2015. View at: Publisher Site | Google Scholar
  31. M. Pulido-Salgado, J. M. Vidal-Taboada, and J. Saura, “C/EBPβ and C/EBPδ transcription factors: Basic biology and roles in the CNS,” Progress in Neurobiology, vol. 132, pp. 1–33, 2015. View at: Publisher Site | Google Scholar
  32. K. Balamurugan and E. Sterneck, “The many faces of C/EBPδ and their relevance for inflammation and cancer,” International Journal of Biological Sciences, vol. 9, no. 9, pp. 917–933, 2013. View at: Publisher Site | Google Scholar
  33. J. Duitman, M. Schouten, A. P. Groot et al., “CCAAT/enhancer-binding protein δ facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 23, pp. 9113–9118, 2012. View at: Publisher Site | Google Scholar
  34. Y. Tie, C. Zhai, Y. Zhang et al., “CCAAT/enhancer-binding protein β overexpression alleviates myocardial remodelling by regulating angiotensin-converting enzyme-2 expression in diabetes,” Journal of Cellular and Molecular Medicine, vol. 22, no. 3, pp. 1475–1488, 2018. View at: Publisher Site | Google Scholar
  35. X. Liu, D. Kwak, Z. Lu et al., “Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling,” Hypertension, vol. 64, no. 4, pp. 738–744, 2014. View at: Publisher Site | Google Scholar
  36. L. Zhang, F. Zhou, X. Yu et al., “C/EBPα deficiency in podocytes aggravates podocyte senescence and kidney injury in aging mice,” Cell Death and Disease, vol. 10, no. 10, p. 684, 2019. View at: Publisher Site | Google Scholar
  37. S. Mei, X. Wang, J. Zhang, J. Qian, and J. Ji, “In vivo transfection of C/EBP-alpha gene could ameliorate CCL(4)-induced hepatic fibrosis in mice,” Hepatology Research, vol. 37, no. 7, pp. 531–539, 2007. View at: Publisher Site | Google Scholar
  38. X. Li, M. Sun, S. Men et al., “The inflammatory transcription factor C/EBPβ plays a critical role in cardiac fibroblast differentiation and a rat model of cardiac fibrosis induced by autoimmune myocarditis,” International Heart Journal, vol. 59, no. 6, pp. 1389–1397, 2018. View at: Publisher Site | Google Scholar
  39. K. C. El Kasmi, S. C. Pugliese, S. R. Riddle et al., “Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension,” Journal of Immunology, vol. 193, no. 2, pp. 597–609, 2014. View at: Publisher Site | Google Scholar
  40. R. Liu, X. Li, Z. Huang et al., “C/EBP homologous protein-induced loss of intestinal epithelial stemness contributes to bile duct ligation-induced cholestatic liver injury in mice,” Hepatology, vol. 67, no. 4, pp. 1441–1457, 2018. View at: Publisher Site | Google Scholar
  41. H. Malhi, E. M. Kropp, V. F. Clavo et al., “C/EBP Homologous Protein-induced Macrophage Apoptosis Protects Mice from Steatohepatitis,” Journal of Biological Chemistry, vol. 288, no. 26, pp. 18624–18642, 2013. View at: Publisher Site | Google Scholar
  42. S. S. Liu, X. X. Lv, C. Liu et al., “Targeting Degradation of the Transcription Factor C/EBPβ Reduces Lung Fibrosis by Restoring Activity of the Ubiquitin-Editing Enzyme A20 in Macrophages,” Immunity, vol. 51, no. 3, pp. 522–534.e7, 2019. View at: Publisher Site | Google Scholar
  43. W. Liu, J. A. Meridew, A. Aravamudhan, G. Ligresti, D. J. Tschumperlin, and Q. Tan, “Targeted regulation of fibroblast state by CRISPR-mediated CEBPA expression,” Respiratory Research, vol. 20, no. 1, p. 281, 2019. View at: Publisher Site | Google Scholar
  44. C. Yan, P. F. Johnson, H. Tang, Y. Ye, M. Wu, and H. Gao, “CCAAT/Enhancer-Binding Protein δ Is a Critical Mediator of Lipopolysaccharide- Induced Acute Lung Injury,” American Journal of Pathology, vol. 182, no. 2, pp. 420–430, 2013. View at: Publisher Site | Google Scholar
  45. A. Burman, J. A. Kropski, C. L. Calvi et al., “Localized hypoxia links ER stress to lung fibrosis through induction of C/EBP homologous protein,” Journal of Clinical Investigation Insight, vol. 3, no. 16, 2018. View at: Publisher Site | Google Scholar
  46. W. H. Landschulz, P. F. Johnson, E. Y. Adashi, B. J. Graves, and S. L. McKnight, “Isolation of a recombinant copy of the gene encoding C/EBP,” Genes and Development, vol. 2, no. 7, pp. 786–800, 1988. View at: Publisher Site | Google Scholar
  47. F. T. Lin, O. A. MacDougald, A. M. Diehl, and M. D. Lane, “A 30-kDa alternative translation product of the CCAAT/enhancer binding protein alpha message: transcriptional activator lacking antimitotic activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 20, pp. 9606–9610, 1993. View at: Publisher Site | Google Scholar
  48. P. Descombes and U. Schibler, “A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the sam mRNA,” Cell, vol. 67, no. 3, pp. 569–579, 1991. View at: Publisher Site | Google Scholar
  49. D. Y. Chih, D. J. Park, M. Gross et al., “Protein partners of C/EBPε,” Experimental Hematology, vol. 32, no. 12, pp. 1173–1181, 2004. View at: Publisher Site | Google Scholar
  50. R. Yamanaka, G. D. Kim, H. S. Radomska et al., “CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 12, pp. 6462–6467, 1997. View at: Publisher Site | Google Scholar
  51. C. F. Calkhoven, C. Muller, and A. Leutz, “Translational control of C/EBPα and C/EBPβ isoform expression,” Genes and Development, vol. 14, no. 15, pp. 1920–1932, 2000. View at: Publisher Site | Google Scholar
  52. W. H. Landschulz, P. F. Johnson, and S. L. McKnight, “The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite,” Science, vol. 243, no. 4899, pp. 1681–1688, 1989. View at: Publisher Site | Google Scholar
  53. A. Khanna-Gupta, “Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBPα),” Blood Cells Molecules and Diseases, vol. 41, no. 1, pp. 77–81, 2008. View at: Publisher Site | Google Scholar
  54. A. Wedel and H. W. Ziegler-Heitbrock, “The C/EBP family of transcription factors,” Immunobiology, vol. 193, no. 2-4, pp. 171–185, 1995. View at: Publisher Site | Google Scholar
  55. N. Kfoury and G. Kapatos, “Identification of neuronal target genes for CCAAT/enhancer binding proteins,” Molecular and Cellular Neuroscience, vol. 40, no. 3, pp. 313–327, 2009. View at: Publisher Site | Google Scholar
  56. J. C. Bartko, Y. Li, G. Sun, and M. W. Halterman, “Phosphorylation within the bipartite NLS alters the localization and toxicity of the ER stress response factor DDIT3/CHOP,” Cell Signalling, vol. 74, p. 109713, 2020. View at: Publisher Site | Google Scholar
  57. S. C. Williams, N. D. Angerer, and P. F. Johnson, “C/EBP proteins contain nuclear localization signals imbedded in their basic regions,” Gene Expression, vol. 6, no. 6, pp. 371–385, 1997. View at: Google Scholar
  58. H. Gao, S. Parkin, P. F. Johnson, and R. C. Schwartz, “C/EBPγ Has a Stimulatory Role on the IL-6 and IL-8 Promoters,” Journal of Biological Chemistry, vol. 277, no. 41, pp. 38827–38837, 2002. View at: Publisher Site | Google Scholar
  59. Y. Huang, L. Lin, Z. Shen et al., “CEBPG promotes esophageal squamous cell carcinoma progression by enhancing PI3K-AKT signaling,” American Journal of Cancer Research, vol. 10, no. 10, pp. 3328–3344, 2020. View at: Google Scholar
  60. M. Ubeda, M. Vallejo, and J. F. Habener, “CHOP enhancement of gene transcription by interactions with Jun/Fos AP-1 complex proteins,” Molecular and Cellular Biology, vol. 19, no. 11, pp. 7589–7599, 1999. View at: Publisher Site | Google Scholar
  61. M. A. Zaini, C. Müller, T. V. de Jong et al., “A p300 and SIRT1 Regulated Acetylation Switch of C/EBPα Controls Mitochondrial Function,” Cell Reports, vol. 22, no. 2, pp. 497–511, 2018. View at: Publisher Site | Google Scholar
  62. T. I. Cesena, T. X. Cui, L. Subramanian et al., “Acetylation and deacetylation regulate CCAAT/enhancer binding protein β at K39 in mediating gene transcription,” Molecular and Cellular Endocrinology, vol. 289, no. 1-2, pp. 94–101, 2008. View at: Publisher Site | Google Scholar
  63. S. Zhou, J. Si, T. Liu, and J. W. DeWille, “PIASy Represses CCAAT/Enhancer-binding Protein δ (C/EBPδ) Transcriptional Activity by Sequestering C/EBPδ to the Nuclear Periphery,” Journal of Biological Chemistry, vol. 283, no. 29, pp. 20137–20148, 2008. View at: Publisher Site | Google Scholar
  64. M. Muraoka, T. Akagi, A. Ueda et al., “C/EBPε ΔRS derived from a neutrophil-specific granule deficiency patient interacts with HDAC1 and its dysfunction is restored by trichostatin A,” Biochemical and Biophysical Research Communications, vol. 516, no. 1, pp. 293–299, 2019. View at: Publisher Site | Google Scholar
  65. N. Ohoka, T. Hattori, M. Kitagawa, K. Onozaki, and H. Hayashi, “Critical and Functional Regulation of CHOP (C/EBP Homologous Protein) through the N-terminal Portion,” Journal of Biological Chemistry, vol. 282, no. 49, pp. 35687–35694, 2007. View at: Publisher Site | Google Scholar
  66. J. Wang, T. R. Sarkar, M. Zhou et al., “CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 37, pp. 16131–16136, 2010. View at: Publisher Site | Google Scholar
  67. P. Li, J. Ge, and H. Li, “Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease,” Nature Reviews Cardiology, vol. 17, no. 2, pp. 96–115, 2020. View at: Publisher Site | Google Scholar
  68. M. Lemos Duarte and L. A. Devi, “Post-translational modifications of opioid receptors,” Trends in Neurosciences, vol. 43, no. 6, pp. 417–432, 2020. View at: Publisher Site | Google Scholar
  69. L. D. Vu, K. Gevaert, and I. De Smet, “Protein language: post-translational modifications talking to each other,” Trends in Plant Science, vol. 23, no. 12, pp. 1068–1080, 2018. View at: Publisher Site | Google Scholar
  70. T. Narita, B. T. Weinert, and C. Choudhary, “Functions and mechanisms of non-histone protein acetylation,” Nature Reviews Molecular and Cellular Biology, vol. 20, no. 3, pp. 156–174, 2019. View at: Publisher Site | Google Scholar
  71. S. J. Humphrey, D. E. James, and M. Mann, “Protein phosphorylation: a major switch mechanism for metabolic regulation,” Trends in Endocrinology and Metabolism, vol. 26, no. 12, pp. 676–687, 2015. View at: Publisher Site | Google Scholar
  72. P. Cohen, “The origins of protein phosphorylation,” Nature Cell Biology, vol. 4, no. 5, pp. E127–E130, 2002. View at: Publisher Site | Google Scholar
  73. I. H. Hong, K. Lewis, P. Iakova et al., “Age-associated Change of C/EBP Family Proteins Causes Severe Liver Injury and Acceleration of Liver Proliferation after CCl4 Treatments,” Journal of Biological Chemistry, vol. 289, no. 2, pp. 1106–1118, 2014. View at: Publisher Site | Google Scholar
  74. G. L. Wang, P. Iakova, M. Wilde, S. Awad, and N. A. Timchenko, “Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP alpha growth inhibitory activity,” Genes and Development, vol. 18, no. 8, pp. 912–925, 2004. View at: Publisher Site | Google Scholar
  75. J. Jin, L. Valanejad, T. P. Nguyen et al., “Activation of CDK4 triggers development of non-alcoholic fatty liver disease,” Cell Reports, vol. 16, no. 3, pp. 744–756, 2016. View at: Publisher Site | Google Scholar
  76. H. Wang, P. Iakova, M. Wilde et al., “C/EBPα Arrests Cell Proliferation through Direct Inhibition of Cdk2 and Cdk4,” Molecular Cell, vol. 8, no. 4, pp. 817–828, 2001. View at: Publisher Site | Google Scholar
  77. M. Bartels, A. M. Govers, V. Fleskens et al., “Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation,” Blood, vol. 125, no. 11, pp. 1782–1792, 2015. View at: Publisher Site | Google Scholar
  78. S. J. van Wijk, S. Fulda, I. Dikic, and M. Heilemann, “Visualizing ubiquitination in mammalian cells,” EMBO Reports, vol. 20, no. 2, p. 46520, 2019. View at: Google Scholar
  79. T. R. Sarkar, S. Sharan, J. Wang et al., “Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBPδ expression and contributes to transformation of breast tumor cells,” Molecular and Cellular Biology, vol. 32, no. 2, pp. 320–332, 2012. View at: Publisher Site | Google Scholar
  80. C. M. Hickey, N. R. Wilson, and M. Hochstrasser, “Function and regulation of SUMO proteases,” Nature Reviews Molecular Cell Biology, vol. 13, no. 12, pp. 755–766, 2012. View at: Publisher Site | Google Scholar
  81. J. M. Wang, C. Y. Ko, L. C. Chen, W. L. Wang, and W. C. Chang, “Functional role of NF-IL6beta and its sumoylation and acetylation modifications in promoter activation of cyclooxygenase 2 gene,” Nucleic Acids Research, vol. 34, no. 1, pp. 217–231, 2006. View at: Publisher Site | Google Scholar
  82. E. M. Cornett, L. Ferry, P. A. Defossez, and S. B. Rothbart, “Lysine methylation regulators moonlighting outside the epigenome,” Molecular Cell, vol. 75, no. 6, pp. 1092–1101, 2019. View at: Publisher Site | Google Scholar
  83. A. Leutz, O. Pless, M. Lappe, G. Dittmar, and E. Kowenz-Leutz, “Crosstalk between phosphorylation and multi-site arginine/lysine methylation in C/EBPs,” Transcription, vol. 2, no. 1, pp. 3–8, 2011. View at: Publisher Site | Google Scholar
  84. E. Kowenz-Leutz, O. Pless, G. Dittmar, M. Knoblich, and A. Leutz, “Crosstalk between C/EBPbeta phosphorylation, arginine methylation, and SWI/SNF/Mediator implies an indexing transcription factor code,” EMBO Journal, vol. 29, no. 6, pp. 1105–1115, 2010. View at: Publisher Site | Google Scholar
  85. Y. E. Leem, J. H. Bae, H. J. Jeong, and J. S. Kang, “PRMT7 deficiency enhances adipogenesis through modulation of C/EBP-β,” Biochemical and Biophysical Research Communications, vol. 517, no. 3, pp. 484–490, 2019. View at: Publisher Site | Google Scholar
  86. P. Boström, N. Mann, J. Wu et al., “C/EBPβ Controls Exercise-Induced Cardiac Growth and Protects against Pathological Cardiac Remodeling,” Cell, vol. 143, no. 7, pp. 1072–1083, 2010. View at: Publisher Site | Google Scholar
  87. P. Xie, L. Sun, B. Nayak et al., “C/EBP-beta modulates transcription of tubulointerstitial nephritis antigen in obstructive uropathy,” Journal of the American Society of Nephrology, vol. 20, no. 4, pp. 807–819, 2009. View at: Publisher Site | Google Scholar
  88. C. Y. Ko, W. C. Chang, and J. M. Wang, “Biological roles of CCAAT/enhancer-binding protein delta during inflammation,” Journal of Biomedical Science, vol. 22, no. 1, p. 6, 2015. View at: Publisher Site | Google Scholar
  89. A. F. Gombart, S. H. Kwok, K. L. Anderson, Y. Yamaguchi, B. E. Torbett, and H. P. Koeffler, “Regulation of neutrophil and eosinophil secondary granule gene expression by transcription factors C/EBP epsilon and PU.1,” Blood, vol. 101, no. 8, pp. 3265–3273, 2003. View at: Publisher Site | Google Scholar
  90. L. L. Tao, Y. Y. Cheng, D. Ding et al., “C/EBP-α ameliorates CCl4-induced liver fibrosis in mice through promoting apoptosis of hepatic stellate cells with little apoptotic effect on hepatocytes in vitro and in vivo,” Apoptosis, vol. 17, no. 5, pp. 492–502, 2012. View at: Publisher Site | Google Scholar
  91. K. Sugahara, K. I. Iyama, T. Kimura et al., “Mice lacking CCAAt/enhancer-binding protein-alpha show hyperproliferation of alveolar type II cells and increased surfactant protein mRNAs,” Cell and Tissue Research, vol. 306, no. 1, pp. 57–63, 2001. View at: Publisher Site | Google Scholar
  92. A. S. Wilhelmson and B. T. Porse, “CCAAT enhancer binding protein alpha (CEBPA) biallelic acute myeloid leukaemia: cooperating lesions, molecular mechanisms and clinical relevance,” British Journal of Haematology, vol. 190, no. 4, pp. 495–507, 2020. View at: Publisher Site | Google Scholar
  93. N. D. Wang, M. J. Finegold, A. Bradley et al., “Impaired energy homeostasis in C/EBP alpha knockout mice,” Science, vol. 269, no. 5227, pp. 1108–1112, 1995. View at: Publisher Site | Google Scholar
  94. L. Guo, X. Li, and Q. Q. Tang, “Transcriptional Regulation of Adipocyte Differentiation: A Central Role for CCAAT/Enhancer-binding Protein (C/EBP) β,” Journal of Biological Chemistry, vol. 290, no. 2, pp. 755–761, 2015. View at: Publisher Site | Google Scholar
  95. S. E. van der Krieken, H. E. Popeijus, R. P. Mensink, and J. Plat, “CCAAT/enhancer binding protein beta in relation to ER stress, inflammation, and metabolic disturbances,” BioMed Research International, vol. 2015, Article ID 324815, 13 pages, 2015. View at: Publisher Site | Google Scholar
  96. H. Nakano, Y. Iida, T. Murase et al., “Co-expression of C/EBPγ and ATF5 in mouse vomeronasal sensory neurons during early postnatal development,” Cell and Tissue Research, vol. 378, no. 3, pp. 427–440, 2019. View at: Publisher Site | Google Scholar
  97. E. A. Ayaub, P. S. Kolb, Z. Mohammed-Ali et al., “GRP78 and CHOP modulate macrophage apoptosis and the development of bleomycin-induced pulmonary fibrosis,” Journal of Pathology, vol. 239, no. 4, pp. 411–425, 2016. View at: Publisher Site | Google Scholar
  98. P. Shyamsunder, M. Shanmugasundaram, A. Mayakonda et al., “Identification of a novel enhancer of CEBPE essential for granulocytic differentiation,” Blood, vol. 133, no. 23, pp. 2507–2517, 2019. View at: Publisher Site | Google Scholar
  99. H. Göös, C. L. Fogarty, B. Sahu et al., “Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy,” Journal of Allergy and Clinical Immunology, vol. 144, no. 5, pp. 1364–1376, 2019. View at: Publisher Site | Google Scholar
  100. J. B. Studd, M. Yang, Z. Li et al., “Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11.2 is mediated by a CEBPE promoter polymorphism,” Leukemia, vol. 33, no. 1, pp. 1–14, 2019. View at: Publisher Site | Google Scholar
  101. A. F. Gombart, M. Shiohara, S. H. Kwok, K. Agematsu, A. Komiyama, and H. P. Koeffler, “Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein--epsilon,” Blood, vol. 97, no. 9, pp. 2561–2567, 2001. View at: Publisher Site | Google Scholar
  102. H. Hu, M. Tian, C. Ding, and S. Yu, “The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection,” Frontiers in Immunology, vol. 9, p. 3083, 2019. View at: Publisher Site | Google Scholar
  103. K. Wook Kang, Y. Gyoon Kim, M. Kyong Cho et al., “Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding protein-mediated stellate cell inactivation,” Federation of American Societies for Experimental Biology Journal, vol. 16, no. 14, pp. 1988–1990, 2002. View at: Publisher Site | Google Scholar
  104. P. Greenwel, S. Tanaka, D. Penkov et al., “Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins,” Molecular and Cellular Biology, vol. 20, no. 3, pp. 912–918, 2000. View at: Publisher Site | Google Scholar
  105. X. Zhao, V. Reebye, P. Hitchen et al., “Mechanisms involved in the activation of C/EBPα by small activating RNA in hepatocellular carcinoma,” Oncogene, vol. 38, no. 18, pp. 3446–3457, 2019. View at: Publisher Site | Google Scholar
  106. G. N. Huang, J. E. Thatcher, J. McAnally et al., “C/EBP transcription factors mediate epicardial activation during heart development and injury,” Science, vol. 338, no. 6114, pp. 1599–1603, 2012. View at: Publisher Site | Google Scholar
  107. X. X. Xu, S. S. Zhang, H. L. Lin et al., “Metformin promotes regeneration of the injured endometrium via inhibition of endoplasmic reticulum stress-induced apoptosis,” Reproductive Sciences, vol. 26, no. 4, pp. 560–568, 2019. View at: Publisher Site | Google Scholar
  108. E. Trefts, M. Gannon, and D. H. Wasserman, “The liver,” Current Biology : CB, vol. 27, no. 21, pp. R1147–R1151, 2017. View at: Publisher Site | Google Scholar
  109. J. Guo, “Research progress on prevention and treatment of glucolipid metabolic disease with integrated traditional Chinese and Western medicine,” Chinese Journal of Integrative Medicine, vol. 23, no. 6, pp. 403–409, 2017. View at: Publisher Site | Google Scholar
  110. S. L. Friedman and M. Pinzani, “Hepatic fibrosis 2022: unmet needs and a blueprint for the future,” Hepatology, vol. 75, no. 2, pp. 473–488, 2022. View at: Publisher Site | Google Scholar
  111. T. Lan, C. Li, G. Yang et al., “Sphingosine kinase 1 promotes liver fibrosis by preventing miR-19b-3p-mediated inhibition of CCR2,” Hepatology, vol. 68, no. 3, pp. 1070–1086, 2018. View at: Publisher Site | Google Scholar
  112. M. Zhao, L. Wang, M. Wang et al., “Targeting fibrosis: mechanisms and clinical trials,” Signal Transduction and Targeted Therapy, vol. 7, no. 1, p. 206, 2022. View at: Publisher Site | Google Scholar
  113. T. Kisseleva and D. Brenner, “Molecular and cellular mechanisms of liver fibrosis and its regression,” Nature Reviews Gastroenterology and Hepatology, vol. 18, no. 3, pp. 151–166, 2021. View at: Publisher Site | Google Scholar
  114. D. Mischoulon, B. Rana, N. L. Bucher, and S. R. Farmer, “Growth-dependent inhibition of CCAAT enhancer-binding protein (C/EBP alpha) gene expression during hepatocyte proliferation in the regenerating liver and in culture,” Molecular and Cellular Biology, vol. 12, no. 6, pp. 2553–2560, 1992. View at: Google Scholar
  115. G. L. Tipoe, T. M. Leung, E. C. Liong, T. Y. Lau, M. L. Fung, and A. A. Nanji, “Epigallocatechin-3-gallate (EGCG) reduces liver inflammation, oxidative stress and fibrosis in carbon tetrachloride (CCl4)-induced liver injury in mice,” Toxicology, vol. 273, no. 1-3, pp. 45–52, 2010. View at: Publisher Site | Google Scholar
  116. N. Kim, S. Choi, C. Lim, H. Lee, and J. Oh, “Albumin mediates PPAR-γ or C/EBP-α-induced phenotypic changes in pancreatic stellate cells,” Biochemical and Biophysical Research Communications, vol. 391, no. 1, pp. 640–644, 2010. View at: Publisher Site | Google Scholar
  117. A. Yoneda, K. Sakai-Sawada, Y. Niitsu, and Y. Tamura, “Vitamin A and insulin are required for the maintenance of hepatic stellate cell quiescence,” Experimental Cell Research, vol. 341, no. 1, pp. 8–17, 2016. View at: Publisher Site | Google Scholar
  118. G. C. Huang, J. S. Zhang, and Q. Q. Tang, “Involvement of C/EBP-α gene in in vitro activation of rat hepatic stellate cells,” Biochemical and Biophysical Research Communications, vol. 324, no. 4, pp. 1309–1318, 2004. View at: Publisher Site | Google Scholar
  119. R. Spinella, R. Sawhney, and R. Jalan, “Albumin in chronic liver disease: structure, functions and therapeutic implications,” Hepatology International, vol. 10, no. 1, pp. 124–132, 2016. View at: Publisher Site | Google Scholar
  120. H. She, S. Xiong, S. Hazra, and H. Tsukamoto, “Adipogenic Transcriptional Regulation of Hepatic Stellate Cells,” Journal of Biological Chemistry, vol. 280, no. 6, pp. 4959–4967, 2005. View at: Publisher Site | Google Scholar
  121. X. Wang, G. Huang, S. Mei, J. Qian, J. Ji, and J. Zhang, “Over-expression of C/EBP-alpha induces apoptosis in cultured rat hepatic stellate cells depending on p53 and peroxisome proliferator-activated receptor-gamma,” Biochemical and Biophysical Research Communications, vol. 380, no. 2, pp. 286–291, 2009. View at: Publisher Site | Google Scholar
  122. D. Ding, L. L. Chen, Y. Z. Zhai et al., “Trichostatin A inhibits the activation of hepatic stellate cells by Increasing C/EBP-alpha acetylation in vivo and in vitro,” Science Report, vol. 8, no. 1, p. 4395, 2018. View at: Publisher Site | Google Scholar
  123. J. Li, M. Ghazwani, Y. Zhang et al., “miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression,” Journal of Hepatology, vol. 58, no. 3, pp. 522–528, 2013. View at: Google Scholar
  124. C. Hou, S. Lu, Y. Su et al., “C/EBP-α induces autophagy by binding to Beclin1 through its own acetylation modification in activated hepatic stellate cells,” Experimental Cell Research, vol. 405, no. 2, article 112721, 2021. View at: Publisher Site | Google Scholar
  125. J. Lekstrom-Himes and K. G. Xanthopoulos, “Biological role of the CCAAT/enhancer-binding protein family of transcription factors,” Journal of Biological Chemistry, vol. 273, no. 44, pp. 28545–28548, 1998. View at: Google Scholar
  126. V. Reebye, P. Saetrom, P. J. Mintz et al., “Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo,” Hepatology, vol. 59, no. 1, pp. 216–227, 2014. View at: Publisher Site | Google Scholar
  127. J. Jin, G. L. Wang, P. Iakova et al., “Epigenetic changes play critical role in age-associated dysfunctions of the liver,” Aging Cell, vol. 9, no. 5, pp. 895–910, 2010. View at: Publisher Site | Google Scholar
  128. H. Okada, R. Takabatake, M. Honda et al., “Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet,” Oncotarget, vol. 8, no. 25, pp. 39978–39993, 2017. View at: Publisher Site | Google Scholar
  129. H. S. Park, J. W. Song, J. H. Park et al., “TXNIP/VDUP1 attenuates steatohepatitis via autophagy and fatty acid oxidation,” Autophagy, vol. 17, no. 9, pp. 2549–2564, 2021. View at: Publisher Site | Google Scholar
  130. H. M. Ni, B. L. Woolbright, J. Williams et al., “Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy,” Journal of Hepatology, vol. 61, no. 3, pp. 617–625, 2014. View at: Publisher Site | Google Scholar
  131. W. J. Kwanten, Y. P. Vandewynckel, W. Martinet et al., “Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice,” American Journal of Physiology Endocrinology, Metabolism and Gastrointestinal Physiology, vol. 311, no. 4, pp. G599–G609, 2016. View at: Publisher Site | Google Scholar
  132. D. Kong, F. Zhang, J. Shao et al., “Curcumin inhibits cobalt chloride-induced epithelial-to-mesenchymal transition associated with interference with TGF-beta/Smad signaling in hepatocytes,” A Journal of Technical Methods and Pathology, vol. 95, no. 11, pp. 1234–1245, 2015. View at: Publisher Site | Google Scholar
  133. D. Kong, Z. Zhang, L. Chen et al., “Curcumin blunts epithelial-mesenchymal transition of hepatocytes to alleviate hepatic fibrosis through regulating oxidative stress and autophagy,” Redox Biology, vol. 36, article 101600, 2020. View at: Publisher Site | Google Scholar
  134. D. M. Gonzalez and D. Medici, “Signaling mechanisms of the epithelial-mesenchymal transition,” Science signaling, vol. 7, no. 344, 2014. View at: Google Scholar
  135. T. Ganz, “Hepcidin in iron metabolism,” Current Opinion in Hematology, vol. 11, no. 4, pp. 251–254, 2004. View at: Google Scholar
  136. D. D. Harrison-Findik, D. Schafer, E. Klein et al., “Alcohol Metabolism-mediated Oxidative Stress Down-regulates Hepcidin Transcription and Leads to Increased Duodenal Iron Transporter Expression,” Journal of Biological Chemistry, vol. 281, no. 32, pp. 22974–22982, 2006. View at: Publisher Site | Google Scholar
  137. K. J. Mehta, S. J. Farnaud, and P. A. Sharp, “Iron and liver fibrosis: mechanistic and clinical aspects,” World Journal of Gastroenterology, vol. 25, no. 5, pp. 521–538, 2019. View at: Google Scholar
  138. R. A. Mir and S. S. Chauhan, “Down regulation of a matrix degrading cysteine protease cathepsin L, by acetaldehyde: role of C/EBPalpha,” Public Library of Science One, vol. 6, no. 6, article 20768, 2011. View at: Google Scholar
  139. J. Reiser, B. Adair, and T. Reinheckel, “Specialized roles for cysteine cathepsins in health and disease,” Journal of Clinical Investigation, vol. 120, no. 10, pp. 3421–3431, 2010. View at: Google Scholar
  140. P. A. Eyers, K. Keeshan, and N. Kannan, “Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease,” Trends in Cell Biology, vol. 27, no. 4, pp. 284–298, 2017. View at: Publisher Site | Google Scholar
  141. E. A. Mack, S. J. Stein, K. S. Rome et al., “Trib1 regulates eosinophil lineage commitment and identity by restraining the neutrophil program,” Blood, vol. 133, no. 22, pp. 2413–2426, 2019. View at: Publisher Site | Google Scholar
  142. P. Nguyen, L. Valanejad, A. Cast et al., “Elimination of Age-Associated Hepatic Steatosis and Correction of Aging Phenotype by Inhibition of cdk4-C/EBPα-p300 Axis,” Cell Reports, vol. 24, no. 6, pp. 1597–1609, 2018. View at: Publisher Site | Google Scholar
  143. B. Guillory, N. Jawanmardi, P. Iakova et al., “Ghrelin deletion protects against age-associated hepatic steatosis by downregulating the C/EBPalpha-p300/DGAT1 pathway,” Aging Cell, vol. 17, no. 1, article 12688, 2018. View at: Publisher Site | Google Scholar
  144. I. P. Pogribny, A. Starlard-Davenport, V. P. Tryndyak et al., “Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice,” Laboratory Investigation, vol. 90, no. 10, pp. 1437–1446, 2010. View at: Publisher Site | Google Scholar
  145. T. Csak, S. Bala, D. Lippai et al., “MicroRNA-155 deficiency attenuates liver steatosis and fibrosis without reducing inflammation in a mouse model of steatohepatitis,” PLoS One, vol. 10, no. 6, article 0129251, 2015. View at: Google Scholar
  146. E. Mirpuri, E. R. Garcia-Trevijano, I. Castilla-Cortazar et al., “Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I,” Iternational Journal of Biochemistry & Cell Biology, vol. 34, no. 3, pp. 242–252, 2002. View at: Publisher Site | Google Scholar
  147. K. R. Aseer, S. W. Kim, M. S. Choi, and J. W. Yun, “Opposite expression of SPARC between the liver and pancreas in streptozotocin-induced diabetic rats,” Plos One, vol. 10, no. 6, article 0131189, 2015. View at: Google Scholar
  148. M. Buck and M. Chojkier, “A ribosomal S-6 kinase-mediated signal to C/EBP-beta is critical for the development of liver fibrosis,” PLoS One, vol. 2, no. 12, article 1372, 2007. View at: Google Scholar
  149. M. Buck, V. Poli, T. Hunter, and M. Chojkier, “C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival,” Molecular Cell, vol. 8, no. 4, pp. 807–816, 2001. View at: Google Scholar
  150. Z. Liu, C. Li, N. Kang, H. Malhi, V. H. Shah, and J. L. Maiers, “Transforming growth factor beta (TGFbeta) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation,” Journal of Biological Chemistry, vol. 294, no. 9, pp. 3137–3151, 2019. View at: Google Scholar
  151. P. Greenwel, J. A. Dominguez-Rosales, G. Mavi, A. M. Rivas-Estilla, and M. Rojkind, “Hydrogen peroxide: a link between acetaldehyde-elicited alpha1(I) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells,” Hepatology, vol. 31, no. 1, pp. 109–116, 2000. View at: Google Scholar
  152. E. R. García‐Trevijano, M. J. Iraburu, L. Fontana et al., “Transforming growth factor beta1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells,” Hepatology, vol. 29, no. 3, pp. 960–970, 1999. View at: Publisher Site | Google Scholar
  153. M. Buck and M. Chojkier, “C/EBPbeta associates with caspase 8 complex proteins and modulates apoptosis in hepatic stellate cells,” Journal of Clinical Gastroenterology, vol. 41, Supplement 3, pp. S295–S299, 2007. View at: Google Scholar
  154. H. W. Park, H. Park, S. H. Ro et al., “Hepatoprotective role of Sestrin2 against chronic ER stress,” Nature Communications, vol. 5, no. 1, p. 4233, 2014. View at: Publisher Site | Google Scholar
  155. Y. Jiang, P. Iakova, J. Jin et al., “Farnesoid X receptor inhibits gankyrin in mouse livers and prevents development of liver cancer,” Hepatology, vol. 57, no. 3, pp. 1098–1106, 2013. View at: Publisher Site | Google Scholar
  156. X. Zhao, J. Fu, A. Xu et al., “Gankyrin drives malignant transformation of chronic liver damage-mediated fibrosis via the Rac1/JNK pathway,” Cell Death and Disease, vol. 6, p. 1751, 2015. View at: Publisher Site | Google Scholar
  157. B. H. Li, F. P. He, X. Yang, Y. W. Chen, and J. G. Fan, “Steatosis induced CCL5 contributes to early-stage liver fibrosis in nonalcoholic fatty liver disease progress,” Translational Research : the Journal of Laboratory and Clinical Medicine, vol. 180, pp. 103–117 e4, 2017. View at: Google Scholar
  158. S. Bala, T. Csak, B. Saha et al., “The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol- induced steatohepatitis,” Journal of Hepatology, vol. 64, no. 6, pp. 1378–1387, 2016. View at: Publisher Site | Google Scholar
  159. J. Lai, S. Jiang, L. Shuai et al., “Comparison of the biological and functional characteristics of mesenchymal stem cells from intrahepatic and identical bone marrow,” Stem Cell Research, vol. 55, article 102477, 2021. View at: Publisher Site | Google Scholar
  160. R. C. Yang, C. Hsu, T. Y. Lee et al., “Transcriptional Regulation of the Group IIA Secretory Phospholipase A2 Gene by C/EBPδ in Rat liver and its Relationship to Hepatic Gluconeogenesis during Sepsis,” Emergency Medicine: Open Access, vol. 3, p. 151, 2013. View at: Google Scholar
  161. R. M. Rai, S. Q. Yang, C. McClain, C. L. Karp, A. S. Klein, and A. M. Diehl, “Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats,” American Journal of Physiology, vol. 270, 6 Part 1, pp. G909–G918, 1996. View at: Google Scholar
  162. M. J. Iraburu, J. A. Domínguez‐Rosales, L. Fontana et al., “Tumor necrosis factor alpha down-regulates expression of the alpha1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPbeta- and C/EBPdelta-dependent mechanism,” Hepatology, vol. 31, no. 5, pp. 1086–1093, 2000. View at: Publisher Site | Google Scholar
  163. Y. Kanamori, M. Murakami, M. Sugiyama, O. Hashimoto, T. Matsui, and M. Funaba, “Interleukin-1beta (IL-1beta) transcriptionally activates hepcidin by inducing CCAAT enhancer-binding protein delta (C/EBPdelta) expression in hepatocytes,” Journal of Biological Chemistry, vol. 292, no. 24, pp. 10275–10287, 2017. View at: Google Scholar
  164. J. Dong, S. Fujii, H. Li et al., “Interleukin-6 and mevastatin regulate plasminogen activator inhibitor-1 through CCAAT/enhancer-binding protein-delta,” Arteriosclerosis Thrombosis and Vascular Biology, vol. 25, no. 5, pp. 1078–1084, 2005. View at: Publisher Site | Google Scholar
  165. A. Tanabe, C. Kumahara, S. Osada, T. Nishihara, and M. Imagawa, “Gene expression of CCAAT/enhancer-binding protein delta mediated by autoregulation is repressed by related gene family proteins,” Biological & pharmaceutical bulletin, vol. 23, no. 12, pp. 1424–1429, 2000. View at: Google Scholar
  166. I. Silva, T. Peccerella, S. Mueller, and V. Rausch, “IL-1 beta-mediated macrophage-hepatocyte crosstalk upregulates hepcidin under physiological low oxygen levels,” Redox Biology, vol. 24, article 101209, 2019. View at: Google Scholar
  167. C. A. Cantwell, E. Sterneck, and P. F. Johnson, “Interleukin-6-specific activation of the C/EBPdelta gene in hepatocytes is mediated by Stat3 and Sp1,” Molecular and Cellular Biology, vol. 18, no. 4, pp. 2108–2117, 1998. View at: Google Scholar
  168. A. K. Ghosh and D. E. Vaughan, “PAI-1 in tissue fibrosis,” Journal of Cellular Physiology, vol. 227, no. 2, pp. 493–507, 2012. View at: Google Scholar
  169. Y. Tanaka, Y. Ishitsuka, M. Hayasaka et al., “The exacerbating roles of CCAAT/enhancer-binding protein homologous protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis and the preventive effects of tauroursodeoxycholic acid (TUDCA) against pulmonary fibrosis in mice,” Pharmacological Research, vol. 99, pp. 52–62, 2015. View at: Publisher Site | Google Scholar
  170. K. Toriguchi, E. Hatano, K. Tanabe et al., “Attenuation of steatohepatitis, fibrosis, and carcinogenesis in mice fed a methionine-choline deficient diet by CCAAT/enhancer-binding protein homologous protein deficiency,” Journal of Gastroenterology and Hepatology, vol. 29, no. 5, pp. 1109–1118, 2014. View at: Publisher Site | Google Scholar
  171. D. DeZwaan-McCabe, J. D. Riordan, A. M. Arensdorf, M. S. Icardi, A. J. Dupuy, and D. T. Rutkowski, “The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis,” Public Library of Science Genetics, vol. 9, no. 12, article 1003937, 2013. View at: Google Scholar
  172. C. Ji, R. Mehrian-Shai, C. Chan, Y. H. Hsu, and N. Kaplowitz, “Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding,” Alcoholism, Clinical and Experimental Research, vol. 29, no. 8, pp. 1496–1503, 2005. View at: Google Scholar
  173. E. Borkham-Kamphorst, B. T. Steffen, E. van de Leur, U. Haas, and R. Weiskirchen, “Portal myofibroblasts are sensitive to CCN-mediated endoplasmic reticulum stress-related apoptosis with potential to attenuate biliary fibrogenesis,” Cell Signal, vol. 51, pp. 72–85, 2018. View at: Google Scholar
  174. K. Kawasaki, R. Ushioda, S. Ito, K. Ikeda, Y. Masago, and K. Nagata, “Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells,” Journal of Biological Chemistry, vol. 290, no. 6, pp. 3639–3646, 2015. View at: Google Scholar
  175. M. P. Lim, L. A. Devi, and R. Rozenfeld, “Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis,” Cell Death and Disease, vol. 2, no. 6, p. 170, 2011. View at: Google Scholar
  176. J. H. Koo, H. J. Lee, W. Kim, and S. G. Kim, “Endoplasmic reticulum stress in hepatic stellate cells promotes liver fibrosis via PERK-mediated degradation of HNRNPA1 and up-regulation of SMAD2,” Gastroenterology, vol. 150, no. 1, pp. 181–193 e8, 2016. View at: Publisher Site | Google Scholar
  177. Q. Zhao, J. Liu, H. Deng et al., “Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output,” Cell, vol. 183, no. 1, pp. 76–93.e22, 2020. View at: Publisher Site | Google Scholar
  178. H. J. Jo, J. W. Yang, J. H. Park et al., “Endoplasmic reticulum stress increases DUSP5 expression via PERK-CHOP pathway, leading to hepatocyte death,” International Journal of Molecular Sciences, vol. 20, no. 18, p. 4369, 2019. View at: Publisher Site | Google Scholar
  179. E. Kao, M. Shinohara, M. Feng, M. Y. Lau, and C. Ji, “Human immunodeficiency virus protease inhibitors modulate Ca2+ homeostasis and potentiate alcoholic stress and injury in mice and primary mouse and human hepatocytes,” Hepatology, vol. 56, no. 2, pp. 594–604, 2012. View at: Google Scholar
  180. N. Tamaki, E. Hatano, K. Taura et al., “CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 294, no. 2, pp. G498–G505, 2008. View at: Publisher Site | Google Scholar
  181. C. Y. Han, H. S. Rho, A. Kim et al., “FXR Inhibits Endoplasmic Reticulum Stress-Induced NLRP3 Inflammasome in Hepatocytes and Ameliorates Liver Injury,” Cell Reports, vol. 24, no. 11, pp. 2985–2999, 2018. View at: Publisher Site | Google Scholar
  182. K. Mueller, Y. Sunami, M. Stuetzle et al., “CHOP-mediated hepcidin suppression modulates hepatic iron load,” Journal of Pathology, vol. 231, no. 4, pp. 532–542, 2013. View at: Publisher Site | Google Scholar
  183. S. Gaul, A. Leszczynska, F. Alegre et al., “Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis,” Journal of Hepatology, vol. 74, no. 1, pp. 156–167, 2021. View at: Publisher Site | Google Scholar
  184. M. Duan, Y. Yang, S. Peng et al., “C/EBP homologous protein (CHOP) activates macrophages and promotes liver fibrosis in Schistosoma japonicum-infected mice,” Journal of Immunology Research, vol. 2019, Article ID 5148575, 13 pages, 2019. View at: Publisher Site | Google Scholar
  185. L. Liu, S. Peng, M. Duan et al., “The role of C/EBP homologous protein (CHOP) in regulating macrophage polarization in RAW264.7 cells,” Microbiology and Immunology, vol. 65, no. 12, pp. 531–541, 2021. View at: Publisher Site | Google Scholar
  186. Z. Rao, J. Sun, X. Pan et al., “Hyperglycemia aggravates hepatic ischemia and reperfusion injury by inhibiting liver-resident macrophage M2 polarization via C/EBP homologous protein-mediated endoplasmic reticulum stress,” Frontiers in Immunology, vol. 8, p. 1299, 2017. View at: Publisher Site | Google Scholar
  187. D. Chanda, E. Otoupalova, S. R. Smith, T. Volckaert, S. P. De Langhe, and V. J. Thannickal, “Developmental pathways in the pathogenesis of lung fibrosis,” Molecular Aspects of Medicine, vol. 65, pp. 56–69, 2019. View at: Google Scholar
  188. M. K. Kang, S. I. Kim, S. Y. Oh, W. Na, and Y. H. Kang, “Tangeretin ameliorates glucose-induced podocyte injury through blocking epithelial to mesenchymal transition caused by oxidative stress and hypoxia,” International Journal of Molecular Sciences, vol. 21, no. 22, p. 8577, 2020. View at: Google Scholar
  189. L. Zhu, T. Yang, L. Li et al., “TSC1 controls macrophage polarization to prevent inflammatory disease,” Nature Communications, vol. 5, no. 1, p. 4696, 2014. View at: Publisher Site | Google Scholar
  190. T. Satoh, K. Nakagawa, F. Sugihara et al., “Identification of an atypical monocyte and committed progenitor involved in fibrosis,” Nature, vol. 541, no. 7635, pp. 96–101, 2017. View at: Publisher Site | Google Scholar
  191. Y. Y. Chu, C. Y. Ko, W. J. Wang et al., “Astrocytic CCAAT/enhancer binding protein δ regulates neuronal viability and spatial learning ability via miR-135a,” Molecular Neurobiology, vol. 53, no. 6, pp. 4173–4188, 2016. View at: Publisher Site | Google Scholar
  192. K. Sugahara, T. Sadohara, M. Sugita, K. Iyama, and M. Takiguchi, “Differential expression of CCAAT enhancer binding protein family in rat alveolar epithelial cell proliferation and in acute lung injury,” Cell and Tissue Research, vol. 297, no. 2, pp. 261–270, 1999. View at: Google Scholar
  193. P. Borger, N. Miglino, M. Baraket, J. L. Black, M. Tamm, and M. Roth, “Impaired translation of CCAAT/enhancer binding protein alpha mRNA in bronchial smooth muscle cells of asthmatic patients,” Journal of Allergy and Clinical Immunology, vol. 123, no. 3, pp. 639–645, 2009. View at: Google Scholar
  194. P. C. Martis, J. A. Whitsett, Y. Xu, A. K. Perl, H. Wan, and M. Ikegami, “C/EBPalpha is required for lung maturation at birth,” Development, vol. 133, no. 6, pp. 1155–1164, 2006. View at: Publisher Site | Google Scholar
  195. A. B. Roos, T. Berg, J. L. Barton, L. Didon, and M. Nord, “Airway epithelial cell differentiation during lung organogenesis requires C/EBPalpha and C/EBPbeta,” Developmental Dynamics: An Official Publication of the American Association of Anatomists, vol. 241, no. 5, pp. 911–923, 2012. View at: Google Scholar
  196. L. Didon, A. B. Roos, G. P. Elmberger, F. J. Gonzalez, and M. Nord, “Lung-specific inactivation of CCAAT/enhancer binding protein alpha causes a pathological pattern characteristic of COPD,” European Respiratory Journal, vol. 35, no. 1, pp. 186–197, 2010. View at: Google Scholar
  197. N. Wang, Q. Li, H. Liu, L. Lin, W. Han, and W. Hao, “Role of C/EBPα hypermethylation in diesel engine exhaust exposure-induced lung inflammation,” Ecotoxicology and Environmental Safety, vol. 183, article 109500, 2019. View at: Publisher Site | Google Scholar
  198. T. Xie, Y. Wang, N. Deng et al., “Single-cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis,” Cell Reports, vol. 22, no. 13, pp. 3625–3640, 2018. View at: Google Scholar
  199. T. Parimon, C. Yao, B. R. Stripp, P. W. Noble, and P. Chen, “Alveolar epithelial type II cells as drivers of lung fibrosis in idiopathic pulmonary fibrosis,” International Journal of Molecular Sciences, vol. 21, no. 7, 2020. View at: Google Scholar
  200. A. Sato, Y. Xu, J. A. Whitsett, and M. Ikegami, “CCAAT/enhancer binding protein-alpha regulates the protease/antiprotease balance required for bronchiolar epithelium regeneration,” American Journal of Respiratory Cell and Molecular Biology, vol. 47, no. 4, pp. 454–463, 2012. View at: Google Scholar
  201. S. Almuntashiri, Y. Zhu, Y. Han, X. Wang, P. R. Somanath, and D. Zhang, “Club cell secreted protein CC16: potential applications in prognosis and therapy for pulmonary diseases,” Journal of Clinical Medicine, vol. 9, no. 12, p. 4039, 2020. View at: Google Scholar
  202. B. Hu, Z. Wu, T. Nakashima, and S. H. Phan, “Mesenchymal-specific deletion of C/EBPbeta suppresses pulmonary fibrosis,” American Journal of Pathology, vol. 180, no. 6, pp. 2257–2267, 2012. View at: Google Scholar
  203. S. Blumer, L. Fang, W. C. Chen et al., “IPF-fibroblast Erk1/2 activity is independent from microRNA cluster 17-92 but can be inhibited by treprostinil through DUSP1,” Cells, vol. 10, no. 11, p. 2836, 2021. View at: Publisher Site | Google Scholar
  204. J. Y. Chen, C. H. Lin, and B. C. Chen, “Hypoxia-induced ADAM 17 expression is mediated by RSK1-dependent C/EBPbeta activation in human lung fibroblasts,” Molecular Immunology, vol. 88, pp. 155–163, 2017. View at: Google Scholar
  205. C. H. Lin, M. C. Yu, W. H. Tung et al., “Connective tissue growth factor induces collagen I expression in human lung fibroblasts through the Rac1/MLK3/JNK/AP-1 pathway,” Biochimica et Biophysica Acta, vol. 1833, no. 12, pp. 2823–2833, 2013. View at: Publisher Site | Google Scholar
  206. X. Yang, F. Qi, S. Wei, L. Lin, and X. Liu, “The transcription factor C/EBPbeta promotes HFL-1 cell migration, proliferation, and inflammation by activating lncRNA HAS2-AS1 in hypoxia,” Frontiers in Cell and Developmental Biology, vol. 9, article 651913, 2021. View at: Google Scholar
  207. D. R. Michael, A. O. Phillips, A. Krupa et al., “The Human Hyaluronan Synthase 2 (HAS2) Gene and Its Natural Antisense RNA Exhibit Coordinated Expression in the Renal Proximal Tubular Epithelial Cell,” Journal of Biological Chemistry, vol. 286, no. 22, pp. 19523–19532, 2011. View at: Publisher Site | Google Scholar
  208. S. D. Collum, N. Y. Chen, A. M. Hernandez et al., “Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis,” British Jornal of Pharmacology, vol. 174, no. 19, pp. 3284–3301, 2017. View at: Publisher Site | Google Scholar
  209. B. Hu, Z. Wu, H. Jin, N. Hashimoto, T. Liu, and S. H. Phan, “CCAAT/enhancer-binding protein beta isoforms and the regulation of alpha-smooth muscle actin gene expression by IL-1 beta,” Journal of Immunology, vol. 173, no. 7, pp. 4661–4668, 2004. View at: Google Scholar
  210. J. Baumert, K. H. Schmidt, A. Eitner, E. Straube, and J. Rodel, “Host cell cytokines induced by Chlamydia pneumoniae decrease the expression of interstitial collagens and fibronectin in fibroblasts,” Infection and Immunity, vol. 77, no. 2, pp. 867–876, 2009. View at: Google Scholar
  211. A. K. Ghosh, S. Bhattacharyya, Y. Mori, and J. Varga, “Inhibition of collagen gene expression by interferon-gamma: novel role of the CCAAT/enhancer binding protein beta (C/EBPbeta),” Journal of Cellular Physiology, vol. 207, no. 1, pp. 251–260, 2006. View at: Google Scholar
  212. S. C. Ou, K. J. Bai, W. H. Cheng et al., “TGF-β induced CTGF expression in human lung epithelial cells through ERK, ADAM17, RSK1, and C/EBPβ pathways,” International Journal of Molecular Sciences, vol. 21, no. 23, p. 9084, 2020. View at: Publisher Site | Google Scholar
  213. H. Ding, J. Chen, J. Qin, R. Chen, and Z. Yi, “TGF-beta-induced alpha-SMA expression is mediated by C/EBPbeta acetylation in human alveolar epithelial cells,” Molecular Medicine, vol. 27, no. 1, p. 22, 2021. View at: Google Scholar
  214. S. Liu, X. Lv, X. Wei et al., “TRIB3–GSK-3 β interaction promotes lung fibrosis and serves as a potential therapeutic target,” Acta Pharmaceutica Sinica B, vol. 11, no. 10, pp. 3105–3119, 2021. View at: Publisher Site | Google Scholar
  215. A. L. Pauleau, R. Rutschman, R. Lang, A. Pernis, S. S. Watowich, and P. J. Murray, “Enhancer-mediated control of macrophage-specific arginase I expression,” Journal of Immunology, vol. 172, no. 12, pp. 7565–7573, 2004. View at: Google Scholar
  216. S. E. Parkin, M. Baer, T. D. Copel, R. C. Schwartz, and P. F. Johnson, “Regulation of CCAAT/enhancer-binding protein (C/EBP) activator proteins by heterodimerization with C/EBPgamma (Ig/EBP),” Journal of Biological Chemistry, vol. 277, no. 26, pp. 23563–23572, 2002. View at: Google Scholar
  217. T. Hattori, N. Ohoka, Y. Inoue, H. Hayashi, and K. Onozaki, “C/EBP family transcription factors are degraded by the proteasome but stabilized by forming dimer,” Oncogene, vol. 22, no. 9, pp. 1273–1280, 2003. View at: Google Scholar
  218. Y. I. Shimizu, M. Morita, A. Ohmi et al., “Fasting induced up-regulation of activating transcription factor 5 in mouse liver,” Life Sciences Part 2, Biochemistry, General and Molecular Biology, vol. 84, no. 25-26, pp. 894–902, 2009. View at: Publisher Site | Google Scholar
  219. C. J. Huggins, M. K. Mayekar, N. Martin et al., “C/EBPγ is a critical regulator of cellular stress response networks through heterodimerization with ATF4,” Molecular and Cellular Biology, vol. 36, no. 5, pp. 693–713, 2015. View at: Publisher Site | Google Scholar
  220. C. J. Huggins, R. Malik, S. Lee et al., “C/EBPγ suppresses senescence and inflammatory gene expression by heterodimerizing with C/EBPβ,” Molecular and Cellular Biology, vol. 33, no. 16, pp. 3242–3258, 2013. View at: Publisher Site | Google Scholar
  221. T. Kaisho, H. Tsutsui, T. Tanaka et al., “Impairment of natural killer cytotoxic activity and interferon gamma production in CCAAT/enhancer binding protein gamma-deficient mice,” Journal of Experimental Medicine, vol. 190, no. 11, pp. 1573–1582, 1999. View at: Publisher Site | Google Scholar
  222. H. M. Yin, L. F. Yan, Q. Liu et al., “Activating transcription factor 3 coordinates differentiation of cardiac and hematopoietic progenitors by regulating glucose metabolism,” Advances, vol. 6, no. 19, article aay9466, 2020. View at: Publisher Site | Google Scholar
  223. C. Yan, L. Zhang, L. Yang, Q. Zhang, and X. Wang, “C/EBPgamma is a critical negative regulator of LPS-/IgG immune complex-induced acute lung injury through the downregulation of C/EBPbeta-/C/EBPdelta-dependent C/EBP transcription activation,” FASEB Journal, vol. 34, no. 10, pp. 13696–13710, 2020. View at: Google Scholar
  224. G. Epstein Shochet, E. Brook, B. Bardenstein-Wald, and D. Shitrit, “TGF-beta pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling,” Respiratory Research, vol. 21, no. 1, p. 56, 2020. View at: Google Scholar
  225. C. Yan, C. Deng, X. Liu et al., “TNF-α induction of IL-6 in alveolar type II epithelial cells: Contributions of JNK/c-Jun/AP-1 element, C/EBPδ/C/EBP binding site and IKK/NF-κB p65/κB site,” Molecular Immunology, vol. 101, pp. 585–596, 2018. View at: Publisher Site | Google Scholar
  226. P. Borger, H. Matsumoto, S. Boustany et al., “Disease-specific expression and regulation of CCAAT/enhancer-binding proteins in asthma and chronic obstructive pulmonary disease,” Journal of Allergy and Clinical Immunology, vol. 119, no. 1, pp. 98–105, 2007. View at: Publisher Site | Google Scholar
  227. M. Lag, E. Skarpen, B. A. W. M. Van Rozendaal, H. P. Haagsman, H. S. Huitfeldt, and E. V. Thrane, “Cell-specific expression of CCAAT/enhancer-binding protein delta (C/EBP delta) in epithelial lung cells,” Experimental Lung Research, vol. 26, no. 5, pp. 383–399, 2000. View at: Publisher Site | Google Scholar
  228. J. Duitman, A. J. Hoogendijk, A. P. Groot et al., “CCAAT-enhancer binding protein delta (C/EBPδ) protects against Klebsiella pneumoniae-induced pulmonary infection: potential role for macrophage migration,” Journal of Infectious Diseases, vol. 206, no. 12, pp. 1826–1835, 2012. View at: Publisher Site | Google Scholar
  229. H. C. Do-Umehara, C. Chen, D. Urich et al., “Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ,” Nature Immunology, vol. 14, no. 5, pp. 461–469, 2013. View at: Publisher Site | Google Scholar
  230. C. Yan, P. A. Ward, X. Wang, and H. Gao, “Myeloid depletion of SOCS3 enhances LPS-induced acute lung injury through CCAAT/enhancer binding protein delta pathway,” FASEB Journal, vol. 27, no. 8, pp. 2967–2976, 2013. View at: Google Scholar
  231. C. Yan, B. Li, X. Liu et al., “Involvement of multiple transcription factors in regulation of IL-β-induced MCP-1 expression in alveolar type II epithelial cells,” Molecular Immunology, vol. 111, pp. 95–105, 2019. View at: Publisher Site | Google Scholar
  232. E. A. Ayaub, A. Dubey, J. Imani et al., “Overexpression of OSM and IL-6 impacts the polarization of pro-fibrotic macrophages and the development of bleomycin-induced lung fibrosis,” Science Report, vol. 7, no. 1, article 13281, 2017. View at: Publisher Site | Google Scholar
  233. T. Tanaka, M. Narazaki, and T. Kishimoto, “IL-6 in inflammation, immunity, and disease,” Cold Spring Harbor Perspectives in Biology, vol. 6, no. 10, article a016295, 2014. View at: Google Scholar
  234. M. Gharaee-Kermani, E. M. Denholm, and S. H. Phan, “Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors,” Journal of Biological Chemistry, vol. 271, no. 30, pp. 17779–17784, 1996. View at: Google Scholar
  235. M. Gharaee-Kermani, R. E. McCullumsmith, I. F. Charo, S. L. Kunkel, and S. H. Phan, “CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis,” Cytokine, vol. 24, no. 6, pp. 266–276, 2003. View at: Google Scholar
  236. T. N. Cassel, L. Nordlund-Moller, O. Andersson, J. A. Gustafsson, and M. Nord, “C/EBPalpha and C/EBPdelta activate the clara cell secretory protein gene through interaction with two adjacent C/EBP-binding sites,” American Journal of Respiratory Cell and Molecular Biology, vol. 22, no. 4, pp. 469–480, 2000. View at: Google Scholar
  237. T. Tomita, T. Kido, R. Kurotani et al., “CAATT/enhancer-binding proteins α and δ interact with NKX2-1 to synergistically activate mouse secretoglobin 3A2 gene expression,” Journal of Biological Chemistry, vol. 283, no. 37, pp. 25617–25627, 2008. View at: Publisher Site | Google Scholar
  238. T. Berg, T. N. Cassel, P. E. Schwarze, and M. Nord, “Glucocorticoids regulate the CCSP and CYP2B1 promoters via C/EBPbeta and delta in lung cells,” Biochemical and Biophysical Research Communications, vol. 293, no. 3, pp. 907–912, 2002. View at: Google Scholar
  239. C. Wendt, K. Tram, A. Price, K. England, A. Stiehm, and A. Panoskaltsis-Mortari, “Club cell secretory protein improves survival in a murine obliterative bronchiolitis model,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 305, no. 9, pp. L642–L650, 2013. View at: Publisher Site | Google Scholar
  240. Y. Cai and S. Kimura, “Secretoglobin 3A2 exhibits anti-fibrotic activity in bleomycin-induced pulmonary fibrosis model mice,” PLoS One, vol. 10, no. 11, article 0142497, 2015. View at: Google Scholar
  241. R. Kurotani, S. Okumura, T. Matsubara et al., “Secretoglobin 3A2 suppresses bleomycin-induced pulmonary fibrosis by transforming growth factor β signaling down-regulation,” Journal of Biological Chemistry, vol. 286, no. 22, pp. 19682–19692, 2011. View at: Publisher Site | Google Scholar
  242. O. Klymenko, M. Huehn, J. Wilhelm et al., “Regulation and role of the ER stress transcription factor CHOP in alveolar epithelial type-II cells,” Journal of Molecular Medicine (Berlin, Germany), vol. 97, no. 7, pp. 973–990, 2019. View at: Publisher Site | Google Scholar
  243. E. Delbrel, A. Soumare, A. Naguez et al., “HIF-1α triggers ER stress and CHOP-mediated apoptosis in alveolar epithelial cells, a key event in pulmonary fibrosis,” Science Report, vol. 8, no. 1, p. 17939, 2018. View at: Publisher Site | Google Scholar
  244. Z. Cao, Q. Xiao, X. Dai et al., “circHIPK2-mediated σ-1R promotes endoplasmic reticulum stress in human pulmonary fibroblasts exposed to silica,” Cell Death and Disease, vol. 8, no. 12, p. 3212, 2017. View at: Publisher Site | Google Scholar
  245. H. S. Hsu, C. C. Liu, J. H. Lin et al., “Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis,” Science Report, vol. 7, no. 1, article 14272, 2017. View at: Publisher Site | Google Scholar
  246. X. Yang, W. Sun, X. Jing, Q. Zhang, H. Huang, and Z. Xu, “C/EBP homologous protein promotes Sonic Hedgehog secretion from type II alveolar epithelial cells and activates Hedgehog signaling pathway of fibroblast in pulmonary fibrosis,” Respiratory Research, vol. 23, no. 1, p. 86, 2022. View at: Google Scholar
  247. J. Hou, J. Ji, X. Chen et al., “Alveolar epithelial cell-derived Sonic Hedgehog promotes pulmonary fibrosis through OPN-dependent alternative macrophage activation,” FEBS Journal, vol. 288, no. 11, pp. 3530–3546, 2021. View at: Publisher Site | Google Scholar
  248. X. Jing, W. Sun, X. Yang et al., “CCAAT/enhancer-binding protein (C/EBP) homologous protein promotes alveolar epithelial cell senescence via the nuclear factor-kappa B pathway in pulmonary fibrosis,” International Journal of Biochemistry and Cell Biology, vol. 143, article 106142, 2022. View at: Publisher Site | Google Scholar
  249. H. Chen, H. Chen, J. Liang et al., “TGF-β1/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency,” Experimental & Molecular Medicine, vol. 52, no. 1, pp. 130–151, 2020. View at: Publisher Site | Google Scholar
  250. Y. C. Chen, B. C. Chen, H. M. Huang, S. H. Lin, and C. H. Lin, “Activation of PERK in ET-1- and thrombin-induced pulmonary fibroblast differentiation: Inhibitory effects of curcumin,” Journal of Cellular Physiology, vol. 234, no. 9, pp. 15977–15988, 2019. View at: Publisher Site | Google Scholar
  251. I. Atanelishvili, J. Liang, T. Akter, D. D. Spyropoulos, R. M. Silver, and G. S. Bogatkevich, “Thrombin increases lung fibroblast survival while promoting alveolar epithelial cell apoptosis via the endoplasmic reticulum stress marker, CCAAT enhancer-binding homologous protein,” American Journal of Respiratory Cell and Molecular Biology, vol. 50, no. 5, pp. 893–902, 2014. View at: Google Scholar
  252. D. R. Lemos and J. S. Duffield, “Tissue-resident mesenchymal stromal cells: implications for tissue-specific antifibrotic therapies,” Science Translational Medicine, vol. 10, no. 426, article eaan5174, 2018. View at: Google Scholar
  253. X. Yang, W. Sun, X. Jing, Q. Zhang, H. Huang, and Z. Xu, “Endoplasmic reticulum stress modulates the fate of lung resident mesenchymal stem cell to myofibroblast via C/EBP homologous protein during pulmonary fibrosis,” Stem Cell Research & Therapy, vol. 13, no. 1, p. 279, 2022. View at: Google Scholar
  254. Y. Yao, Y. Wang, Z. Zhang et al., “Chop deficiency protects mice against bleomycin-induced pulmonary fibrosis by attenuating M2 macrophage production,” Molecular Therapy, vol. 24, no. 5, pp. 915–925, 2016. View at: Publisher Site | Google Scholar
  255. B. D. Humphreys, “Mechanisms of renal fibrosis,” Annual Review of Physiology, vol. 80, pp. 309–326, 2018. View at: Google Scholar
  256. S. Hu, H. Hu, R. Wang, H. He, and H. Shui, “MicroRNA-29b prevents renal fibrosis by attenuating renal tubular epithelial cell-mesenchymal transition through targeting the PI3K/AKT pathway,” International Urology and Nephrology, vol. 53, no. 9, pp. 1941–1950, 2021. View at: Google Scholar
  257. J. Wei, Z. Xu, and X. Yan, “The role of the macrophage-to-myofibroblast transition in renal fibrosis,” Frontiers in Immunology, vol. 13, article 934377, 2022. View at: Google Scholar
  258. J. Rustenhoven, L. C. Smyth, D. Jansson et al., “Modelling physiological and pathological conditions to study pericyte biology in brain function and dysfunction,” BMC Neuroscience, vol. 19, no. 1, p. 6, 2018. View at: Publisher Site | Google Scholar
  259. F. Zhong, W. Wang, K. Lee, J. C. He, and N. Chen, “Role of C/EBP-alpha in adriamycin-induced podocyte injury,” Science Report, vol. 6, article 33520, 2016. View at: Google Scholar
  260. T. C. Lin, T. C. Lee, S. L. Hsu, and C. S. Yang, “The molecular mechanism of leptin secretion and expression induced by aristolochic acid in kidney fibroblast,” PLoS One, vol. 6, no. 2, article 16654, 2011. View at: Google Scholar
  261. P. Kumpers, F. Gueler, S. Rong et al., “Leptin is a coactivator of TGF-beta in unilateral ureteral obstructive kidney disease,” American Journal of Physiology-Renal Physiology, vol. 293, no. 4, pp. F1355–F1362, 2007. View at: Publisher Site | Google Scholar
  262. N. Toda, M. Mukoyama, M. Yanagita, and H. Yokoi, “CTGF in kidney fibrosis and glomerulonephritis,” Inflammation and Regeneration, vol. 38, p. 14, 2018. View at: Google Scholar
  263. K. Fujiu, I. Manabe, and R. Nagai, “Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice,” Journal of Clinical Investigation, vol. 121, no. 9, pp. 3425–3441, 2011. View at: Google Scholar
  264. X. M. Meng, T. S. Mak, and H. Y. Lan, “Macrophages in renal fibrosis,” Advances in Experimental Medicine and Biology, vol. 1165, pp. 285–303, 2019. View at: Google Scholar
  265. C. E. Witherel, D. Abebayehu, T. H. Barker, and K. L. Spiller, “Macrophage and fibroblast interactions in biomaterial-mediated fibrosis,” Advanced Healthcare Materials, vol. 8, no. 4, article 1801451, 2019. View at: Google Scholar
  266. W. X. Yang, Y. Liu, S. M. Zhang et al., “Epac activation ameliorates tubulointerstitial inflammation in diabetic nephropathy,” Acta Pharmacologica Sinica, vol. 43, no. 3, pp. 659–671, 2022. View at: Publisher Site | Google Scholar
  267. H. Ding, F. Bai, H. Cao et al., “PDE/cAMP/Epac/C/EBP-β signaling cascade regulates mitochondria biogenesis of tubular epithelial cells in renal fibrosis,” Antioxidants and Redox Signaling, vol. 29, no. 7, pp. 637–652, 2018. View at: Publisher Site | Google Scholar
  268. Y. Li, Y. Liu, Y. Huang et al., “IRF-1 promotes renal fibrosis by downregulation of Klotho,” FASEB Journal, vol. 34, no. 3, pp. 4415–4429, 2020. View at: Publisher Site | Google Scholar
  269. R. Khosrokhavar, R. Dizaji, F. Nazari, A. Sharafi, J. Tajkey, and M. J. Hosseini, “The role of PGC-1alpha and metabolic signaling pathway in kidney injury following chronic administration with 3-MCPD as a food processing contaminant,” Journal of Food Biochemistry, vol. 45, no. 6, article 13744, 2021. View at: Google Scholar
  270. Y. Liu, X. Bi, J. Xiong et al., “MicroRNA-34a promotes renal fibrosis by downregulation of Klotho in tubular epithelial cells,” Molecular Therapy, vol. 27, no. 5, pp. 1051–1065, 2019. View at: Publisher Site | Google Scholar
  271. X. Hu, Y. Xu, Z. Zhang et al., “TSC1 affects the process of renal ischemia-reperfusion injury by controlling macrophage polarization,” Frontiers in Immunology, vol. 12, article 637335, 2021. View at: Publisher Site | Google Scholar
  272. X. Li, S. Yang, M. Yan et al., “Interstitial HIF1A induces an estimated glomerular filtration rate decline through potentiating renal fibrosis in diabetic nephropathy,” Life sciences Part 2, Biochemistry, General and Molecular Biology, vol. 241, article 117109, 2020. View at: Publisher Site | Google Scholar
  273. J. Yamaguchi, T. Tanaka, N. Eto, and M. Nangaku, “Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein delta,” Kidney International, vol. 88, no. 2, pp. 262–275, 2015. View at: Google Scholar
  274. R. L. Granger, T. R. Hughes, and D. P. Ramji, “Stimulus- and cell-type-specific regulation of CCAAT-enhancer binding protein isoforms in glomerular mesangial cells by lipopolysaccharide and cytokines,” Biochimica et Biophysica Acta, vol. 1501, no. 2-3, pp. 171–179, 2000. View at: Google Scholar
  275. K. Miyoshi, T. Okura, T. Fukuoka, and J. Higaki, “CCAAT/enhancer-binding protein-delta is induced in mesangial area during the early stages of anti-Thy1.1 glomerulonephritis and regulates cell proliferation and inflammatory gene expression in cultured rat mesangial cells,” Clinical and Experimental Nephrology, vol. 11, no. 1, pp. 26–33, 2007. View at: Google Scholar
  276. M. Takeji, N. Kawada, T. Moriyama et al., “CCAAT/enhancer-binding protein delta contributes to myofibroblast transdifferentiation and renal disease progression,” Journal of the American Society of Nephrology : JASN, vol. 15, no. 9, pp. 2383–2390, 2004. View at: Publisher Site | Google Scholar
  277. M. Liu, X. Ning, R. Li et al., “Signalling pathways involved in hypoxia-induced renal fibrosis,” Journal of Cellular and Molecular Medicine, vol. 21, no. 7, pp. 1248–1259, 2017. View at: Publisher Site | Google Scholar
  278. W. Lv, G. W. Booz, Y. Wang, F. Fan, and R. J. Roman, “Inflammation and renal fibrosis: recent developments on key signaling molecules as potential therapeutic targets,” European Journal of Pharmacology, vol. 820, pp. 65–76, 2018. View at: Google Scholar
  279. Z. Gai, T. Gui, C. Hiller, and G. A. Kullak-Ublick, “Farnesoid X receptor protects against kidney injury in uninephrectomized obese mice,” Journal of Biological Chemistry, vol. 291, no. 5, pp. 2397–2411, 2016. View at: Google Scholar
  280. X. Liang, N. Duan, Y. Wang et al., “Advanced oxidation protein products induce endothelial-to-mesenchymal transition in human renal glomerular endothelial cells through induction of endoplasmic reticulum stress,” Journal of Diabetes and Its Complications, vol. 30, no. 4, pp. 573–579, 2016. View at: Publisher Site | Google Scholar
  281. C. K. Chiang, S. P. Hsu, C. T. Wu et al., “Endoplasmic reticulum stress implicated in the development of renal fibrosis,” Molecular Medicine, vol. 17, no. 11-12, article 17111295, pp. 1295–1305, 2011. View at: Publisher Site | Google Scholar
  282. M. Zhang, Y. Guo, H. Fu et al., “Chop deficiency prevents UUO-induced renal fibrosis by attenuating fibrotic signals originated from Hmgb1/TLR4/NFkappaB/IL-1beta signaling,” Cell Death and Disease, vol. 6, no. 8, p. 1847, 2015. View at: Publisher Site | Google Scholar
  283. Z. Mohammed-Ali, C. Lu, M. K. Marway et al., “Endoplasmic reticulum stress inhibition attenuates hypertensive chronic kidney disease through reduction in proteinuria,” Science Report, vol. 7, no. 1, article 41572, 2017. View at: Publisher Site | Google Scholar
  284. J. Wu, R. Zhang, M. Torreggiani et al., “Induction of diabetes in aged C57B6 mice results in severe nephropathy: an association with oxidative stress, endoplasmic reticulum stress, and inflammation,” American Journal of Pathology, vol. 176, no. 5, pp. 2163–2176, 2010. View at: Publisher Site | Google Scholar
  285. M. R. Noh, C. H. Woo, M. J. Park, J. In Kim, and K. M. Park, “Ablation of C/EBP homologous protein attenuates renal fibrosis after ureteral obstruction by reducing autophagy and microtubule disruption,” Biochimica et Biophysica Acta, Molecular Basis of Disease, vol. 1864, no. 5 Part A, pp. 1634–1641, 2018. View at: Google Scholar
  286. W. Guo, J. Ding, A. Zhang et al., “The inhibitory effect of quercetin on asymmetric dimethylarginine-induced apoptosis is mediated by the endoplasmic reticulum stress pathway in glomerular endothelial cells,” International Journal of Molecular Sciences, vol. 15, no. 1, pp. 484–503, 2014. View at: Publisher Site | Google Scholar
  287. S. J. Marciniak, C. Y. Yun, S. Oyadomari et al., “CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum,” Genes and Development, vol. 18, no. 24, pp. 3066–3077, 2004. View at: Publisher Site | Google Scholar
  288. S. Kumar, G. Wang, N. A. Zheng et al., “HIMF (hypoxia-induced mitogenic factor)-IL (interleukin)-6 signaling mediates cardiomyocyte-fibroblast crosstalk to promote cardiac hypertrophy and fibrosis,” Hypertension, vol. 73, no. 5, pp. 1058–1070, 2019. View at: Google Scholar
  289. V. Esposito, F. Grosjean, J. Tan et al., “CHOP deficiency results in elevated lipopolysaccharide-induced inflammation and kidney injury,” American Journal of Physiology Renal, fluid and Electrolyte Physiology, vol. 304, no. 4, pp. F440–F450, 2013. View at: Publisher Site | Google Scholar
  290. B. López, S. Ravassa, M. U. Moreno et al., “Diffuse myocardial fibrosis: mechanisms, diagnosis and therapeutic approaches,” Nature Reviews Cardiology, vol. 18, no. 7, pp. 479–498, 2021. View at: Publisher Site | Google Scholar
  291. N. G. Frangogiannis, “Cardiac fibrosis: cell biological mechanisms, molecular pathways and therapeutic opportunities,” Molecular Aspects of Medicine, vol. 65, pp. 70–99, 2019. View at: Google Scholar
  292. H. C. Suh, T. Benoukraf, P. Shyamsunder et al., “LPS independent activation of the pro-inflammatory receptor Trem1 by C/EBPepsilon in granulocytes,” Science Report, vol. 7, article 46440, 2017. View at: Google Scholar
  293. L. Wang, H. Wu, Y. Deng et al., “FTZ ameliorates diabetic cardiomyopathy by inhibiting inflammation and cardiac fibrosis in the streptozotocin-induced model,” Evidence-Based Complementary and Alternative Medicine, vol. 2021, Article ID 5582567, 16 pages, 2021. View at: Publisher Site | Google Scholar
  294. Y. Chen, Y. Chang, N. Zhang, X. Guo, G. Sun, and Y. Sun, “Atorvastatin attenuates myocardial hypertrophy in spontaneously hypertensive rats via the C/EBPbeta/PGC-1alpha/UCP3 pathway,” Cellular Physiology and Biochemistry, vol. 46, no. 3, pp. 1009–1018, 2018. View at: Google Scholar
  295. V. Palau, J. Pascual, M. J. Soler, and M. Riera, “Role of ADAM17 in kidney disease,” American Journal of Physiology-Renal Physiology, vol. 317, no. 2, pp. F333–F342, 2019. View at: Google Scholar
  296. S. J. Forrester, G. W. Booz, C. D. Sigmund et al., “Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology,” Physiological Reviews, vol. 98, no. 3, pp. 1627–1738, 2018. View at: Google Scholar
  297. P. P. Hao, J. M. Yang, M. X. Zhang et al., “Angiotensin-(1-7) treatment mitigates right ventricular fibrosis as a distinctive feature of diabetic cardiomyopathy,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 308, no. 9, pp. H1007–H1019, 2015. View at: Google Scholar
  298. H. Xiao, C. S. Piao, R. F. Chen, and Y. Y. Zhang, “AMP-activated kinase activation inhibits transforming growth factor-beta1 production in cardiac fibroblasts via targeting C/EBPbeta,” Sheng Li Xue Bao (Acta Physiologica Sinica), vol. 69, no. 2, pp. 123–128, 2017. View at: Google Scholar
  299. W. Briest, B. Rassler, A. Deten et al., “Norepinephrine-induced interleukin-6 increase in rat hearts: differential signal transduction in myocytes and non-myocytes,” Pflugers Archiv (European Journal of Physiology), vol. 446, no. 4, pp. 437–446, 2003. View at: Google Scholar
  300. S. Akira, H. Isshiki, T. Sugita et al., “A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family,” EMBO Journal, vol. 9, no. 6, pp. 1897–1906, 1990. View at: Publisher Site | Google Scholar
  301. C. Ambrosino, T. Iwata, C. Scafoglio, M. Mallardo, R. Klein, and A. R. Nebreda, “TEF-1 and C/EBPbeta are major p38alpha MAPK-regulated transcription factors in proliferating cardiomyocytes,” Biochemical Journal, vol. 396, no. 1, pp. 163–172, 2006. View at: Google Scholar
  302. S. Rius-Perez, I. Torres-Cuevas, I. Millan, A. L. Ortega, and S. Perez, “PGC-1alpha, inflammation, and oxidative stress: an integrative view in metabolism,” Oxidative Medicine and Cellular Longevity, vol. 2020, Article ID 1452696, 20 pages, 2020. View at: Publisher Site | Google Scholar
  303. B. Zhang, Y. Tan, Z. Zhang et al., “Novel PGC-1alpha/ATF5 axis partly activates UPR(mt) and mediates cardioprotective role of tetrahydrocurcumin in pathological cardiac hypertrophy,” Oxidative Medicine and Cellular Longevity, vol. 2020, Article ID 9187065, 21 pages, 2020. View at: Publisher Site | Google Scholar
  304. H. Saito, C. Patterson, Z. Hu et al., “Expression and self-regulatory function of cardiac interleukin-6 during endotoxemia,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 279, no. 5, pp. H2241–H2248, 2000. View at: Publisher Site | Google Scholar
  305. L. Sun, Y. Ke, C. Y. Zhu et al., “Inflammatory reaction versus endogenous peroxisome proliferator-activated receptors expression, re-exploring secondary organ complications of spontaneously hypertensive rats,” Chinese Medical Journal, vol. 121, no. 22, pp. 2305–2311, 2008. View at: Google Scholar
  306. J. Zhang, L. Chang, C. Chen et al., “Rad GTPase inhibits cardiac fibrosis through connective tissue growth factor,” Cardiovascular Research, vol. 91, no. 1, pp. 90–98, 2011. View at: Google Scholar
  307. I. Shimizu and T. Minamino, “Physiological and pathological cardiac hypertrophy,” Journal of Molecular and Cellular Cardiology, vol. 97, pp. 245–262, 2016. View at: Google Scholar
  308. B. Zhang, P. Zhang, Y. Tan et al., “C1q-TNF-related protein-3 attenuates pressure overload-induced cardiac hypertrophy by suppressing the p38/CREB pathway and p38-induced ER stress,” Cell Death and Disease, vol. 10, no. 7, p. 520, 2019. View at: Publisher Site | Google Scholar
  309. H. Peng, J. Xu, X. P. Yang et al., “N-acetyl-seryl-aspartyl-lysyl-proline treatment protects heart against excessive myocardial injury and heart failure in mice,” Cell Canadian Journal of Physiology and Pharmacology, vol. 97, no. 8, pp. 753–765, 2019. View at: Google Scholar
  310. J. Hu, X. Lu, X. Zhang et al., “Exogenous spermine attenuates myocardial fibrosis in diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress and the canonical Wnt signaling pathway,” Cell Biology International, vol. 44, no. 8, pp. 1660–1670, 2020. View at: Google Scholar
  311. H. Y. Fu, K. Okada, Y. Liao et al., “Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload,” Circulation, vol. 122, no. 4, pp. 361–369, 2010. View at: Publisher Site | Google Scholar
  312. G. Luo, Q. Li, X. Zhang et al., “Ablation of C/EBP homologous protein increases the acute phase mortality and doesn't attenuate cardiac remodeling in mice with myocardial infarction,” Biochemical and Biophysical Research Communications, vol. 464, no. 1, pp. 201–207, 2015. View at: Publisher Site | Google Scholar
  313. M. Kassan, K. Ait-Aissa, E. Radwan et al., “Essential role of smooth muscle STIM1 in hypertension and cardiovascular dysfunction,” Arteriosclerosis Thrombosis and Vascular Biology, vol. 36, no. 9, pp. 1900–1909, 2016. View at: Publisher Site | Google Scholar
  314. Y. Wang, T. Lei, J. Yuan et al., “GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and myocardial oxidative stress,” Redox Biology, vol. 17, pp. 25–34, 2018. View at: Google Scholar
  315. X. M. Wang, Y. C. Wang, X. J. Liu et al., “BRD7 mediates hyperglycaemia-induced myocardial apoptosis via endoplasmic reticulum stress signalling pathway,” Journal of Cellular and Molecular Medicine, vol. 21, no. 6, pp. 1094–1105, 2017. View at: Google Scholar
  316. F. Olivares-Silva, J. Espitia-Corredor, A. Letelier et al., “TGF-beta1 decreases CHOP expression and prevents cardiac fibroblast apoptosis induced by endoplasmic reticulum stress,” Toxicology In Vitro, vol. 70, article 105041, 2021. View at: Google Scholar
  317. F. V. Souza-Neto, S. Jiménez-González, B. Delgado-Valero et al., “The interplay of mitochondrial oxidative stress and endoplasmic reticulum stress in cardiovascular fibrosis in obese rats,” Antioxidants (Basel), vol. 10, no. 8, p. 1274, 2021. View at: Google Scholar
  318. Y. Li, M. Dong, Q. Wang et al., “HIMF deletion ameliorates acute myocardial ischemic injury by promoting macrophage transformation to reparative subtype,” Basic Research in Cardiology, vol. 116, no. 1, p. 30, 2021. View at: Publisher Site | Google Scholar
  319. H. Kawano, J. Kimura-Kuroda, Y. Komuta et al., “Role of the lesion scar in the response to damage and repair of the central nervous system,” Cell and Tissue Research, vol. 349, no. 1, pp. 169–180, 2012. View at: Publisher Site | Google Scholar
  320. M. Ayazi, S. Zivkovic, G. Hammel, B. Stefanovic, and Y. Ren, “Fibrotic scar in CNS injuries: from the cellular origins of fibroblasts to the molecular processes of fibrotic scar formation,” Cells, vol. 11, no. 15, p. 2371, 2022. View at: Google Scholar
  321. S. Okada, M. Hara, K. Kobayakawa, Y. Matsumoto, and Y. Nakashima, “Astrocyte reactivity and astrogliosis after spinal cord injury,” Neuroscience Research, vol. 126, pp. 39–43, 2018. View at: Google Scholar
  322. R. Li, R. Strohmeyer, Z. Liang, L. F. Lue, and J. Rogers, “CCAAT/enhancer binding protein delta (C/EBPdelta) expression and elevation in Alzheimer's disease,” Neurobiology of Aging, vol. 25, no. 8, pp. 991–999, 2004. View at: Google Scholar
  323. T. Valente, M. Straccia, N. Gresa-Arribas et al., “CCAAT/enhancer binding protein δ regulates glial proinflammatory gene expression,” Neurobiology of Aging, vol. 34, no. 9, pp. 2110–2124, 2013. View at: Publisher Site | Google Scholar
  324. M. Nedergaard, B. Ransom, and S. A. Goldman, “New roles for astrocytes: redefining the functional architecture of the brain,” Trends in Neurosciences, vol. 26, no. 10, pp. 523–530, 2003. View at: Google Scholar
  325. M. V. Sofroniew, “Astrocyte reactivity: subtypes, states, and functions in CNS innate immunity,” Trends in Immunology, vol. 41, no. 9, pp. 758–770, 2020. View at: Google Scholar
  326. L. W. Lau, R. Cua, M. B. Keough, S. Haylock-Jacobs, and V. W. Yong, “Pathophysiology of the brain extracellular matrix: a new target for remyelination,” Nature Reviews Neuroscience, vol. 14, no. 10, pp. 722–729, 2013. View at: Publisher Site | Google Scholar
  327. G. A. Rosenberg, “Extracellular matrix inflammation in vascular cognitive impairment and dementia,” Clinical Science (London), vol. 131, no. 6, pp. 425–437, 2017. View at: Google Scholar
  328. S. M. Wang, J. C. Hsu, C. Y. Ko et al., “Astrocytic CCAAT/enhancer-binding protein delta contributes to glial scar formation and impairs functional recovery after spinal cord injury,” Molecular Neurobiology, vol. 53, no. 9, pp. 5912–5927, 2016. View at: Publisher Site | Google Scholar
  329. C. Y. Ko, Y. Y. Chu, S. Narumiya et al., “The CCAAT/enhancer-binding protein delta/miR135a/thrombospondin 1 axis mediates PGE2-induced angiogenesis in Alzheimer's disease,” Neurobiology of Aging, vol. 36, no. 3, pp. 1356–1368, 2015. View at: Publisher Site | Google Scholar
  330. C. Bruder, M. Hagleitner, G. Darlington et al., “HIV-1 induces complement factor C3 synthesis in astrocytes and neurons by modulation of promoter activity,” Molecular Immunology, vol. 40, no. 13, pp. 949–961, 2004. View at: Publisher Site | Google Scholar
  331. C. S. McCauslin, V. Heath, A. M. Colangelo et al., “CAAT/Enhancer-binding Protein δ and cAMP-response Element-binding Protein Mediate Inducible Expression of the Nerve Growth Factor Gene in the Central Nervous System,” Journal of Biological Chemistry, vol. 281, no. 26, pp. 17681–17688, 2006. View at: Publisher Site | Google Scholar
  332. A. Kale, N. M. Rogers, and K. Ghimire, “Thrombospondin-1 CD47 signalling: from mechanisms to medicine,” International Journal of Molecular Sciences, vol. 22, no. 8, p. 4062, 2021. View at: Google Scholar
  333. D. R. Mathern and P. S. Heeger, “Molecules great and small: the complement system,” Clin Journal of the American Society of Nephrology, vol. 10, no. 9, pp. 1636–1650, 2015. View at: Google Scholar
  334. P. Liu, S. Li, and L. Tang, “Nerve growth factor: a potential therapeutic target for lung diseases,” International Journal of Molecular Sciences, vol. 22, no. 17, p. 9112, 2021. View at: Google Scholar
  335. E. A. Winkler, J. D. Sengillo, R. D. Bell, J. Wang, and B. V. Zlokovic, “Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability,” Journal of Cerebral Blood Flow and Metabolism, vol. 32, no. 10, pp. 1841–1852, 2012. View at: Google Scholar
  336. D. O. Dias, J. Kalkitsas, Y. Kelahmetoglu et al., “Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions,” Nature Communications, vol. 12, no. 1, p. 5501, 2021. View at: Publisher Site | Google Scholar
  337. W. Cai, H. Liu, J. Zhao et al., “Pericytes in brain injury and repair after ischemic stroke,” Translational Stroke Research, vol. 8, no. 2, pp. 107–121, 2017. View at: Publisher Site | Google Scholar
  338. J. Rustenhoven, E. L. Scotter, D. Jansson et al., “An anti-inflammatory role for C/EBPδ in human brain pericytes,” Science Report, vol. 5, no. 1, article 12132, 2015. View at: Publisher Site | Google Scholar
  339. Y. Li, X. He, R. Kawaguchi et al., “Microglia-organized scar-free spinal cord repair in neonatal mice,” Nature, vol. 587, no. 7835, pp. 613–618, 2020. View at: Publisher Site | Google Scholar
  340. S. Apolloni and N. D'Ambrosi, “Fibrosis as a common trait in amyotrophic lateral sclerosis tissues,” Neural regeneration research, vol. 17, no. 1, pp. 97-98, 2022. View at: Google Scholar
  341. M. A. A. Mahdy, “Skeletal muscle fibrosis: an overview,” Cell and Tissue Research, vol. 375, no. 3, pp. 575–588, 2019. View at: Google Scholar
  342. J. W. Von den Hoff, P. L. Carvajal Monroy, E. M. Ongkosuwito, T. H. van Kuppevelt, and W. F. Daamen, “Muscle fibrosis in the soft palate: delivery of cells, growth factors and anti-fibrotics,” Advanced Drug Delivery Reviews, vol. 146, pp. 60–76, 2019. View at: Google Scholar
  343. K. Garg, B. T. Corona, and T. J. Walters, “Therapeutic strategies for preventing skeletal muscle fibrosis after injury,” Frontiers in Pharmacology, vol. 6, p. 87, 2015. View at: Google Scholar
  344. S. A. Manea, A. Todirita, M. Raicu, and A. Manea, “C/EBP transcription factors regulate NADPH oxidase in human aortic smooth muscle cells,” Journal of Cellular and Molecular Medicine, vol. 18, no. 7, pp. 1467–1477, 2014. View at: Google Scholar
  345. W. T. Chuang, C. C. Yen, C. S. Huang, H. W. Chen, and C. K. Lii, “Benzyl isothiocyanate ameliorates high-fat diet-induced hyperglycemia by enhancing Nrf2-dependent antioxidant defense-mediated IRS-1/AKT/TBC1D1 signaling and GLUT4 expression in skeletal muscle,” Journal of Agricultural and Food Chemistry, vol. 68, no. 51, pp. 15228–15238, 2020. View at: Google Scholar
  346. M. E. Davis, M. A. Korn, J. P. Gumucio et al., “Simvastatin reduces fibrosis and protects against muscle weakness after massive rotator cuff tear,” Journal of Shoulder and Elbow Surgery, vol. 24, no. 2, pp. 280–287, 2015. View at: Publisher Site | Google Scholar
  347. A. F. Pagano, R. Demangel, T. Brioche et al., “Muscle regeneration with intermuscular adipose tissue (IMAT) accumulation is modulated by mechanical constraints,” PloS One, vol. 10, no. 12, article 0144230, 2015. View at: Google Scholar
  348. L. Zhang, J. Pan, Y. Dong et al., “Stat3 Activation Links a C/EBPδ to Myostatin Pathway to Stimulate Loss of Muscle Mass,” Cell Metabolism, vol. 18, no. 3, pp. 368–379, 2013. View at: Publisher Site | Google Scholar
  349. K. A. Silva, J. Dong, Y. Dong et al., “Inhibition of Stat3 Activation Suppresses Caspase-3 and the Ubiquitin- Proteasome System, Leading to Preservation of Muscle Mass in Cancer Cachexia,” Journal of Biological Chemistry, vol. 290, no. 17, pp. 11177–11187, 2015. View at: Publisher Site | Google Scholar
  350. M. A. Winslow and S. E. Hall, “Muscle wasting: A review of exercise, classical and non-classical RAS axes,” Journal of Cellular and Molecular Medicine, vol. 23, no. 9, pp. 5836–5845, 2019. View at: Google Scholar
  351. Y. Hasegawa, “New perspectives on obesity-induced adipose tissue fibrosis and related clinical manifestations,” Endocrine Journal, vol. 69, no. 7, pp. 739–748, 2022. View at: Google Scholar
  352. K. Sun, J. Tordjman, K. Clement, and P. E. Scherer, “Fibrosis and adipose tissue dysfunction,” Cell Metabolism, vol. 18, no. 4, pp. 470–477, 2013. View at: Google Scholar
  353. V. Jan, P. Cervera, M. Maachi et al., “Altered fat differentiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1-infected lipodystrophic patients,” Antiviral Therapy, vol. 9, no. 4, pp. 555–564, 2004. View at: Publisher Site | Google Scholar
  354. C. Bing, S. Russell, E. Becket et al., “Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice,” British Journal of Cancer, vol. 95, no. 8, pp. 1028–1037, 2006. View at: Publisher Site | Google Scholar
  355. J. Cai, B. Li, K. Liu, J. Feng, K. Gao, and F. Lu, “Low-dose G-CSF improves fat graft retention by mobilizing endogenous stem cells and inducing angiogenesis, whereas high-dose G-CSF inhibits adipogenesis with prolonged inflammation and severe fibrosis,” Biochemical and Biophysical Research Communications, vol. 491, no. 3, pp. 662–667, 2017. View at: Google Scholar
  356. J. Yamaguchi, T. Tanaka, H. Saito et al., “Echinomycin inhibits adipogenesis in 3T3-L1 cells in a HIF-independent manner,” Science Report, vol. 7, no. 1, p. 6516, 2017. View at: Publisher Site | Google Scholar
  357. N. Halberg, T. Khan, M. E. Trujillo et al., “Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue,” Molecular and Cellular Biology, vol. 29, no. 16, pp. 4467–4483, 2009. View at: Publisher Site | Google Scholar
  358. M. F. Griffin, J. Huber, F. J. Evan, N. Quarto, and M. T. Longaker, “The role of Wnt signaling in skin fibrosis,” Medicinal Research Reviews, vol. 42, no. 1, pp. 615–628, 2022. View at: Google Scholar
  359. Y. Tai, E. L. Woods, J. Dally et al., “Myofibroblasts: function, formation, and scope of molecular therapies for skin fibrosis,” Biomolecules, vol. 11, no. 8, p. 1095, 2021. View at: Publisher Site | Google Scholar
  360. H. E. Talbott, S. Mascharak, M. Griffin, D. C. Wan, and M. T. Longaker, “Wound healing, fibroblast heterogeneity, and fibrosis,” Cell Stem Cell, vol. 29, no. 8, pp. 1161–1180, 2022. View at: Google Scholar
  361. H. Ikeda, T. Sunazuka, H. Suzuki et al., “EM703, the new derivative of erythromycin, inhibits transcription of type I collagen in normal and scleroderma fibroblasts,” Journal of Dermatological Science, vol. 49, no. 3, pp. 195–205, 2008. View at: Google Scholar
  362. R. Melchionna, G. Bellavia, M. Romani et al., “C/EBPγ Regulates Wound Repair and EGF Receptor Signaling,” Journal of Investigative Dermatology, vol. 132, no. 7, pp. 1908–1917, 2012. View at: Publisher Site | Google Scholar
  363. S. Werner, T. Krieg, and H. Smola, “Keratinocyte-fibroblast interactions in wound healing,” Journal of Investigative Dermatology, vol. 127, no. 5, pp. 998–1008, 2007. View at: Google Scholar
  364. P. Bainbridge, “Wound healing and the role of fibroblasts,” Journal of Wound Care, vol. 22, no. 8, pp. 410–412, 2013. View at: Google Scholar
  365. R. A. Ignotz and J. Massague, “Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix,” Journal of Biological Chemistry, vol. 261, no. 9, pp. 4337–4345, 1986. View at: Google Scholar
  366. C. H. Ong, C. L. Tham, H. H. Harith, N. Firdaus, and D. A. Israf, “TGF-beta-induced fibrosis: a review on the underlying mechanism and potential therapeutic strategies,” European Journal of Pharmacology, vol. 911, article 174510, 2021. View at: Google Scholar
  367. Y. T. Chen, F. W. Chen, T. H. Chang et al., “Hepatoma-derived growth factor supports the antiapoptosis and profibrosis of pancreatic stellate cells,” Cancer Letters, vol. 457, pp. 180–190, 2019. View at: Publisher Site | Google Scholar
  368. M. Fu, D. Peng, T. Lan, Y. Wei, and X. Wei, “Multifunctional regulatory protein connective tissue growth factor (CTGF): a potential therapeutic target for diverse diseases,” Acta Pharmaceutica Sinica B, vol. 12, no. 4, pp. 1740–1760, 2022. View at: Google Scholar
  369. X. Shi-wen, L. A. Stanton, L. Kennedy et al., “CCN2 Is Necessary for Adhesive Responses to Transforming Growth Factor-β1 in Embryonic Fibroblasts,” Journal of Biological Chemistry, vol. 281, no. 16, pp. 10715–10726, 2006. View at: Publisher Site | Google Scholar
  370. B. A. Janowski, S. T. Younger, D. B. Hardy, R. Ram, K. E. Huffman, and D. R. Corey, “Activating gene expression in mammalian cells with promoter-targeted duplex RNAs,” Nature Chemical Biology, vol. 3, no. 3, pp. 166–173, 2007. View at: Google Scholar
  371. J. Voutila, P. Sætrom, P. Mintz et al., “Gene expression profile changes after short-activating RNA-mediated induction of endogenous pluripotency factors in human mesenchymal stem cells,” Molecular Therapy Nucleic Acids, vol. 1, no. 8, p. 5, 2012. View at: Google Scholar
  372. L. Zheng, L. Wang, J. Gan, and H. Zhang, “RNA activation: promise as a new weapon against cancer,” Cancer Letters, vol. 355, no. 1, pp. 18–24, 2014. View at: Google Scholar
  373. J. W. Zhang, Q. Q. Tang, C. Vinson, and M. D. Lane, “Dominant-negative C/EBP disrupts mitotic clonal expansion and differentiation of 3T3-L1 preadipocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 1, pp. 43–47, 2004. View at: Google Scholar
  374. F. Zhang, C. Lu, W. Xu et al., “Curcumin raises lipid content by Wnt pathway in hepatic stellate cell,” Journal of Surgical Research, vol. 200, no. 2, pp. 460–466, 2016. View at: Publisher Site | Google Scholar
  375. Y. N. Lamb, “Nintedanib: a review in fibrotic interstitial lung diseases,” Drugs, vol. 81, no. 5, pp. 575–586, 2021. View at: Google Scholar
  376. S. M. Ruwanpura, B. J. Thomas, and P. G. Bardin, “Pirfenidone: molecular mechanisms and potential clinical applications in lung disease,” American Journal of Respiratory Cell and Molecular Biology, vol. 62, no. 4, pp. 413–422, 2020. View at: Google Scholar
  377. L. G. N. de Almeida, H. Thode, Y. Eslambolchi et al., “Matrix metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology,” Pharmacological Reviews, vol. 74, no. 3, pp. 712–768, 2022. View at: Publisher Site | Google Scholar
  378. J. Huynh, A. Chand, D. Gough, and M. Ernst, “Therapeutically exploiting STAT3 activity in cancer - using tissue repair as a road map,” Nature Reviews Cancer, vol. 19, no. 2, pp. 82–96, 2019. View at: Google Scholar
  379. V. Krishnan and Y. Ito, “A regulatory role for RUNX1, RUNX3 in the maintenance of genomic integrity,” Advances in Experimental Medicine and Biology, vol. 962, pp. 491–510, 2017. View at: Google Scholar
  380. A. Glanz, S. Chakravarty, M. Varghese et al., “Transcriptional, and non-transcriptional activation, posttranslational modifications, and antiviral functions of interferon regulatory factor 3 and viral antagonism by the SARS-Coronavirus,” Viruses, vol. 13, no. 4, p. 575, 2021. View at: Publisher Site | Google Scholar
  381. N. R. Ortega Rodriguez, M. T. Audicana Berasategui, B. de la Hoz Caballer, and A. Valero Santiago, “The century of mRNA vaccines: COVID-19 vaccines and allergy,” Journal of Investigational Allergology and Clinical Immunology, vol. 31, no. 1, pp. 89–91, 2021. View at: Google Scholar
  382. Y. Wang, Z. Zhang, J. Luo, X. Han, Y. Wei, and X. Wei, “mRNA vaccine: a potential therapeutic strategy,” Molecular Cancer, vol. 20, no. 1, p. 33, 2021. View at: Publisher Site | Google Scholar
  383. J. Q. Huang, H. Zhang, X. W. Guo et al., “Mechanically activated calcium channel PIEZO1 modulates radiation-induced epithelial-mesenchymal transition by forming a positive feedback with TGF-beta1,” Frontiers in Molecular Biosciences, vol. 8, p. 725275, 2021. View at: Publisher Site | Google Scholar
  384. T. Zhou, L. Wang, K. Y. Zhu et al., “Dominant-negative C/ebpα and polycomb group protein Bmi1 extend short-lived hematopoietic stem/progenitor cell life span and induce lethal dyserythropoiesis,” Blood, vol. 118, no. 14, pp. 3842–3852, 2011. View at: Publisher Site | Google Scholar
  385. X. J. Song, C. Y. Yang, B. Liu et al., “Atorvastatin inhibits myocardial cell apoptosis in a rat model with post-myocardial infarction heart failure by downregulating ER stress response,” International Journal of Medical Sciences, vol. 8, no. 7, pp. 564–572, 2011. View at: Publisher Site | Google Scholar
  386. T. Senoo, R. Sasaki, Y. Akazawa et al., “Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice,” BioMed Central Gastroenterology, vol. 18, no. 1, p. 34, 2018. View at: Publisher Site | Google Scholar
  387. N. Adel, E. M. Mantawy, D. A. El-Sherbiny, and E. El-Demerdash, “Iron chelation by deferasirox confers protection against concanavalin A-induced liver fibrosis: a mechanistic approach,” Toxicology and Applied Pharmacology, vol. 382, article 114748, 2019. View at: Google Scholar
  388. H. S. Guan, H. J. Shangguan, Z. Shang, L. Yang, X. M. Meng, and S. B. Qiao, “Endoplasmic reticulum stress caused by left ventricular hypertrophy in rats: effects of telmisartan,” American Journal of the Medical Sciences, vol. 342, no. 4, pp. 318–323, 2011. View at: Google Scholar
  389. H. Lee, R. Kang, Y. Hahn et al., “Antiobesity effect of baicalin involves the modulations of proadipogenic and antiadipogenic regulators of the adipogenesis pathway,” Phytotherapy Research, vol. 23, no. 11, pp. 1615–1623, 2009. View at: Publisher Site | Google Scholar
  390. L. O. Dannenberg and H. J. Edenberg, “Epigenetics of gene expression in human hepatoma cells: expression profiling the response to inhibition of DNA methylation and histone deacetylation,” BioMed Central Genomics, vol. 7, p. 181, 2006. View at: Google Scholar
  391. S. Gao, L. Li, L. Li et al., “Effects of the combination of tanshinone IIA and puerarin on cardiac function and inflammatory response in myocardial ischemia mice,” Journal of Molecular and Cellular Cardiology, vol. 137, pp. 59–70, 2019. View at: Publisher Site | Google Scholar
  392. J. Gilmer, T. Harding, L. Woods, B. Black, R. Flores, and J. Pfau, “Mesothelial cell autoantibodies upregulate transcription factors associated with fibrosis,” Inhalation Toxicology, vol. 29, no. 1, pp. 10–17, 2017. View at: Google Scholar
  393. T. C. Weng, C. C. Shen, Y. T. Chiu, Y. L. Lin, and Y. T. Huang, “Effects of armepavine against hepatic fibrosis induced by thioacetamide in rats,” Phytotherapy Research, vol. 26, no. 3, pp. 344–353, 2012. View at: Google Scholar
  394. N. Gresa-Arribas, J. Serratosa, J. Saura, and C. Sola, “Inhibition of CCAAT/enhancer binding protein delta expression by chrysin in microglial cells results in anti-inflammatory and neuroprotective effects,” Journal of Neurochemistry, vol. 115, no. 2, pp. 526–536, 2010. View at: Google Scholar
  395. H. Chen, J. Tao, J. Wang, and L. Yan, “Artesunate prevents knee intraarticular adhesion via PRKR-like ER kinase (PERK) signal pathway,” Journal of Orthopaedic Surgery and Research, vol. 14, no. 1, p. 448, 2019. View at: Google Scholar
  396. B. San‐Miguel, I. Crespo, D. I. Sánchez et al., “Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis,” Journal of Pineal Research, vol. 59, no. 2, pp. 151–162, 2015. View at: Publisher Site | Google Scholar
  397. S. S. Li, J. M. Ye, Z. Y. Deng, L. X. Yu, X. X. Gu, and Q. F. Liu, “Ginsenoside-Rg1 inhibits endoplasmic reticulum stress-induced apoptosis after unilateral ureteral obstruction in rats,” Renal Failure, vol. 37, no. 5, pp. 890–895, 2015. View at: Google Scholar
  398. B. Li, J. Tian, Y. Sun et al., “Activation of NADPH oxidase mediates increased endoplasmic reticulum stress and left ventricular remodeling after myocardial infarction in rabbits,” Biochimica et Biophysica Acta, vol. 1852, no. 5, pp. 805–815, 2015. View at: Google Scholar
  399. C. W. Younce, J. Niu, J. Ayala et al., “Exendin-4 improves cardiac function in mice overexpressing monocyte chemoattractant protein-1 in cardiomyocytes,” Journal of Molecular and Cellular Cardiology, vol. 76, pp. 172–176, 2014. View at: Publisher Site | Google Scholar
  400. X. Li, S. Wang, J. Dai et al., “Homoharringtonine prevents surgery-induced epidural fibrosis through endoplasmic reticulum stress signaling pathway,” European Journal of Pharmacology, vol. 815, pp. 437–445, 2017. View at: Publisher Site | Google Scholar

Copyright © 2022 Lexun Wang et al. Exclusive Licensee Science and Technology Review Publishing House. Distributed under a Creative Commons Attribution License (CC BY 4.0).

 PDF Download Citation Citation
Views227
Downloads180
Altmetric Score
Citations