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Review

The Role of Interferon Regulatory Factors in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

by
Chunye Zhang
1,†,
Shuai Liu
2,† and
Ming Yang
3,*,†
1
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65212, USA
2
The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, China
3
Department of Surgery, University of Missouri, Columbia, MO 65211, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Gastroenterol. Insights 2022, 13(2), 148-161; https://doi.org/10.3390/gastroent13020016
Submission received: 27 March 2022 / Revised: 19 April 2022 / Accepted: 21 April 2022 / Published: 26 April 2022
(This article belongs to the Section Liver)
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Abstract

:
Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease with many metabolic comorbidities, such as obesity, diabetes, and cardiovascular diseases. Non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, accompanies the progression of hepatic steatosis, inflammation, cell death, and varying degree of liver fibrosis. Interferons (IFNs) have been shown to play important roles in the pathogenesis of NAFLD and NASH. Their regulating transcriptional factors such as interferon regulatory factors (IRFs) can regulate IFN expression, as well as genes involved in macrophage polarization, which are implicated in the pathogenesis of NAFLD and advanced liver disease. In this review, the roles of IRF-involved signaling pathways in hepatic inflammation, insulin resistance, and immune cell activation are reviewed. IRFs such as IRF1 and IRF4 are also involved in the polarization of macrophages that contribute to critical roles in NAFLD or NASH pathogenesis. In addition, IRFs have been shown to be regulated by treatments including microRNAs, PPAR modulators, anti-inflammatory agents, and TLR agonists or antagonists. Modulating IRF-mediated factors through these treatments in chronic liver disease can ameliorate the progression of NAFLD to NASH. Furthermore, adenoviruses and CRISPR activation plasmids can also be applied to regulate IRF-mediated effects in chronic liver disease. Pre-clinical and clinical trials for evaluating IRF regulators in NAFLD treatment are essential in the future direction.

1. Introduction

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease, accompanying the increased incidence of comorbidities, such as obesity, diabetes, and cardiovascular diseases. By 2030, NAFLD will affect more than 100 million people in the United States [1], posing a tremendous economic burden. The more severe form of NAFLD is non-alcoholic steatohepatitis (NASH) with the progression of liver inflammation and varying degrees of fibrosis, which can progress to cirrhosis and hepatocellular carcinoma (HCC) [2,3,4]. In addition, NAFLD may progress to HCC without the development of NASH or cirrhosis [5]. Factors such as sedentary lifestyle and overnutrition (consumption of high fructose) can cause NAFLD and its progression [6,7,8]. Although many clinical trials for evaluating NAFLD treatment options, there is no currently approved treatment [9]. Molecular signaling pathways involved in liver inflammation, cell death, and fibrosis account for the progression of NAFLD [10,11]. In addition, hepatic metabolic dysfunctions and syndromes such as lipid accumulation and insulin resistance are associated with the progression of NAFLD to NASH and late-stage liver disease [12]. Therefore, a better understanding of the underlying cellular and molecular mechanisms of NAFLD pathogenesis is essential for the development of novel therapeutic strategies.
Interferons (IFNs) have been shown to play important roles in hepatic inflammation, fibrogenesis, and lipid accumulation. For example, feeding a methionine- and choline-deficient high-fat (MCDHF) diet induced more severe liver steatosis and inflammation on day 42 and advanced liver fibrosis on day 70 in IFN-γ-deficient, compared with wild-type mice [13]. In vitro study further showed that IFN-γ can stimulate the inflammatory response of macrophages and subsequent activation of hepatic stellate cells (HSCs), the collagen-producing cells in the liver, resulting in the progression of liver fibrosis [13]. Another study showed that IFN-γ was involved in the cytotoxicity of natural killer (NK) cells against HSCs in both mice and humans to attenuate liver fibrosis, which can be induced by activation of glutamate and metabotropic glutamate receptor 5 (mGluR5) in NK cells [14]. In addition, IFN-γ was upregulated in the NASH liver of rats, which promoted Toll-like receptor 2 (TLR2)-induced progression of liver inflammation [15].
Interferon regulatory factors (IRFs), a family of transcription factors that regulate IFN expression, play important roles in both innate and adaptive immune responses [16,17,18]. IRFs bind together with other transcriptional factors (e.g., signal transducer and activator of transcription/STAT, PU.1/Spi-1 proto-oncogene, and nuclear factor-kappa B/NF-κB) in the nucleus to regulate target gene expression [19]. IRF1 was initially found to regulate type I interferon secretion, including interferons alpha and beta (IFN-α and IFN-β) [20]. To date, it has been shown that there are nine members in the IRF family in humans and mice [21]. Compared with the white adipose tissue, liver tissue had higher mRNA expression levels of IRFs except for IRF4 in FVB mice [22]. IRFs have been shown to be involved in the regulation of adipogenesis and adipose tissue inflammation [23,24], renal fibrosis [25,26], and cell death [27,28]. Moreover, accumulating studies show that IRFs play important roles in chronic liver diseases [29,30,31,32], including NAFLD and NASH. In this review, we focus on the discussion of the roles IRFs in NAFLD and NASH pathogenesis. In addition, IRFs-mediated treatments are reviewed to illustrate the potential of IRF regulators in NAFLD treatment.

2. Interferons in NAFLD and NASH

Accumulating studies show that IFNs play pivotal roles in NAFLD and its progression to NASH, including type I, II, and III interferons. One study showed that the expression of type I interferon (IFN-I) was upregulated in human patients with NAFLD, which was positively associated with the number of CD8+ T cells [33]. Meanwhile, hepatic IFN-α protein level was found to increase in obese mice with activation of IRFs [33]. Another study showed that high levels of IFN-I induced apoptosis of regulatory T cells (Tregs), resulting in aggravation of NASH in mice [34]. Therefore, mice with depletion of IFN-α receptor 1 in CD8+ T cells were protected from the development of fatty liver disease [33]. In addition, NASH development was inhibited in IFN-α/β receptor 1-deficient mice than in wild-type mice [34]. In contrast, another study showed that treatment with IFN-α2b ameliorated obesity-associated NAFLD development in mice fed with a high-fat diet (HFD), resulting in a reduction in liver inflammation and cholesterol accumulation by increasing fatty acid oxidation [35]. IRFs and TLRs are involved in the effect of IFNs on NAFLD or NASH by regulating IFN expression. For example, IRF7-deficient mice challenged with lipopolysaccharides (LPS) expressed low levels of IFN-β and IFN-β-induced pro-inflammatory cytokine such as interleukin (IL)-1β [36]. This study further showed that IRF3/7-mediated the production of IFN-β was dependent on the signaling pathway TIR-domain-containing adapter-inducing interferon-β (TRIF) but not MyD88 (myeloid differentiation primary response 88) signaling in LPS-activated macrophages [36]. In human plasmacytoid dendritic cells (pDCs), IRF5, and NF-κBp50 are important co-regulators for the expression of IFN-β and IL-6, which can be induced by activation of TLR9 [37].
IFN-γ is the only member of type II interferon. Hart et al. reported that IFN-γ-deficiency mice developed NASH more quickly, compared with wild-type mice on HFD, with the progression of transforming growth factor-β (TGF-β)-induced liver fibrosis [38]. IFN-γ was also upregulated in rat NASH liver, which was associated with TLR2-mediated liver inflammation [15]. TLR2/MyD88/NF-κB signaling pathway has been shown to be involved in T-cell activation and IFN-γ production [39]. Activation of IRF5 in CD4+ T cells can induce the production of Th1- and Th17-associated cytokines including IFN-γ, as well as chemokine receptors such as CCR5 (C-C chemokine receptor type 5) and CXCR4 (C-X-C motif chemokine receptor 4) but inhibit Th2-associated cytokines in mice [40]. Interestingly, another study showed that serum levels of IFN-α2 but not IFN-γ were increased in obese patients with hepatic steatosis [41]. These results show that hepatic IFN-γ expression is positively associated with NASH progression, compared with serum IFN-γ concertation. The role of circulating IFN-γ in NAFLD remains to be explored.
Type III interferons consist of four IFN-λ molecules—namely, IFN-λ1–4, known as antiviral cytokines. It has been demonstrated that serum levels of IFN-λ3 were increased in patients with chronic hepatitis C, compared with that in healthy controls, which was positively associated with the severity of liver fibrosis [42]. In addition, the rs368234815 TT allele on the IFN-λ4 locus was independently associated with advanced liver fibrosis, the severity of liver necroinflammation, and NASH [43]. CpG DNAs can stimulate TLR9 in murine pDCs via MyD88/TRAF6/TRAF3/IRF7/8 signaling pathway to regulate IFNα/β/λ secretion [44]. A graphic picture lists the signaling pathways of how TLR2, TLR4, TLR9, and IRFs regulate the production of IFNs (Figure 1).
Furthermore, IFN binding with IFN receptors can result in feedback regulation of IRF/IFN signaling in diseases [45,46,47]. Overall, IFNs are involved in the NAFLD/NASH pathogenesis, and their expression can be regulated by transcriptional factors including IRFs [48,49]. The roles of IRFs will be further discussed in the following section.

3. Roles of IRFs in NAFLD and NASH

The roles of IRFs in the pathogenesis of NAFLD and NASH are diverse. Herein, we discuss all nine members of IRF in liver inflammation, fibrogenesis, and cell death, which are closely associated with the progression of NAFLD to NASH.

3.1. IRF1

IFN-γ, which was highly expressed in rat NASH liver, induced the activation of transcriptional factors phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and IRF1, resulting in upregulation of liver inflammation [15]. In addition, the expression of IRF1 in macrophages can be induced by IFN-γ (Figure 2), synergizing with NF-κB to induce M1-like macrophages with the production of IL-12, inducible nitric oxide synthase (iNOS), and IFN-β [50,51]. Seidman et al. reported that the expression of IRF1 was dramatically reduced in Kupffer cells (KCs), liver resident macrophages, from NASH livers, compared with that in livers of normal mice [52]. In contrast, both IRF7 and IRF8 were increased in KCs from NASH livers, compared with that in normal livers [29]. These results show that KCs in the NASH liver may downregulate IRF1 expression to suppress liver inflammation.

3.2. IRF2

IRF2 shows an anti-inflammatory function in macrophages. Knockdown of IRF2 accelerated LPS-induced activation of macrophages by regulating hypoxia-inducible factor 1-alpha (HIF-1α)-dependent glycolysis [53]. In addition, IRF2 binding protein 2 (IRF2BP2) was significantly decreased in the fatty liver [54]. Specific knockdown of IRF2BP2 in hepatocytes aggravated HFD-induced hepatic steatosis, inflammation, and insulin resistance, indicating a protective role of IRF2BP2 in NAFLD. In contrast, overexpression of IRF2BP2 can inhibit these processes [54].

3.3. IRF3

Globally knocking out IRF3 dramatically promoted diet-induced hepatic steatosis and insulin resistance, whereas overexpression of IRF3 mediated by adenoviruses promoted a balance of energy metabolism, such as glucose and lipid [55]. In addition, the molecular study showed that the effect of IRF3 on hepatic steatosis was mediated by inhibition of the nuclear factor-kappa B kinase subunit beta (IKKβ)/NF-κB signaling pathway [55]. Inhibiting IKKβ/NF-κB signaling pathway has been shown to inhibit HFD-induced obesity and its comorbidities [56]. Accumulating studies show that IKKβ plays an essential role in the development and progression of cardiometabolic diseases [57]. Furthermore, IKKβ/NF-κB signaling pathway has also been reported to be involved in hypothalamic inflammation [58]. Therefore, activation of IRF3 can inhibit IKKβ/NF-κB signaling pathway to ameliorate NAFLD and other metabolic disorders.

3.4. IRF4

In macrophages (Figure 2), IL-4 can induce M2 macrophage polarization by activating IRF4 signaling to prevent IRF5-mediated M1 macrophage polarization [59]. In addition, IRF4 is required for the mTORC2-mediated signaling pathway during M2 macrophage polarization [60]. In obesity, IRF4 is required for Treg differentiation except for basic leucine zipper transcription factor activating transcription factor-like (BATF), peroxisome proliferator-activated receptor gamma (PPAR-γ), and IL-33 [61]. IL-21 has been reported to be a negative regulator of IRF4, and IL-21-deficient mice decreased fat accumulation and liver inflammation [62], indicating a protective role of IRF4 in NAFLD. In vitro study also showed that IRF4 plays an important role in IL-4 induced expression of extracellular matrix proteins, such as α-smooth muscle actin (α-SMA), as well as the transition of M2-like macrophages from mouse bone marrow-derived monocytes to myofibroblasts [25].

3.5. IRF5

The expression of IRF5 was increased in adipose tissue associated with metabolic syndrome in patients with obesity or type 2 diabetes [63]. In addition, the expression of IRF5 was positively correlated with inflammatory markers (e.g., TNF-α and IL-23A), which may function as a marker of metabolic inflammation. Alzaid et al. reported that IRF5 was upregulated in hepatic macrophages from human patients with liver fibrosis induced by NAFLD or hepatitis C virus infection [64]. Mice with IRF5 knockdown in myeloid cells were protected from metabolic stress or toxin-induced liver fibrosis, compared with wild-type controls [64]. In addition, IRF5 expression was positively associated with proinflammatory cytokines such as TNF, IL-1β, and IL-6, and was negatively associated with anti-inflammatory cytokines such as IL-10 and profibrotic gene TGF-β1. Meanwhile, IRF5 has been shown to be highly expressed in M1 macrophages (pro-inflammatory phenotype) to activate the expression of IL-12p40, IL-12p35, and IL-23p19 and to suppress IL-10 expression (M2-like macrophage secreting cytokine) [65]. IRF5-deficient mice displayed an accumulation of subcutaneous white adipose tissue, compared with wild-type mice. Moreover, IRF5 deficiency promoted the alternative polarization of macrophages (M2-like macrophages), which was associated with insulin sensitivity and collagen production in visceral adipose tissue [66].

3.6. IRF6

IRF6 was significantly decreased in HFD-induced fatty liver. A cellular mechanism study showed that knockout IRF6 specifically in hepatocytes accelerated liver steatosis, while overexpression of IRF6 in hepatocytes ameliorated liver steatosis [67]. A molecular mechanism study exhibited that IRF6 can directly bind to the promoter of the peroxisome proliferator-activated receptor γ (PPARγ) gene, resulting in suppression of PPARγ expression and its targeted genes to inhibit lipid accumulation [67].

3.7. IRF7

The expression of IRF7 was upregulated in liver tissue of diet-induced obese mice and genetically obese (ob/ob) mice, compared with that in lean controls [68]. IRF7-deficient mice displayed less body weight, insulin sensitivity, hepatic macrophage infiltration, inflammation, and steatosis, compared with wild-type controls [68]. A complex formed by MyD88, TRAF6, and IRF7 is required for TLR-mediated IFN-α expression, and IRF7 activation requires the ubiquitin E3 ligase activity of TRAF6 [69].

3.8. IRF8

Together with IRF1, IRF8 plays an essential role in IFN-γ induced activation of macrophages, as well as the function of myeloid cells [70]. Loss of IRF8 may cause more severe infection, as it regulates the expression of antimicrobial and inflammatory genes in mice with neuroinflammation or pulmonary tuberculosis [71,72]. Knocking down IRF8 in zebrafish caused a reduction in macrophage numbers and the number and activation of hepatic stellate cells [73,74]. The Notch/RBPJ (recombination signal binding protein for immunoglobulin kappa J region) signaling can control the expression of IRF8 to modulate M1 macrophage cytokine expression [75].

3.9. IRF9

Interestingly, Wang et al. reported that IRF9 displayed a contrary role in obese mice compared to IRF7. The hepatic expression of IRF9 was decreased in the liver tissues of obese mice, compared with that in lean controls [76]. IRF9 knockout (KO) mice showed increased insulin resistance, hepatic steatosis, and inflammation compared to wild-type controls while feeding HFD. In contrast, overexpression of IRF9 mediated by adenoviruses significantly improved the metabolic syndrome in HFD-fed mice or ob/ob obese mice [76].
Overall, IRFs show diverse functions in fatty liver, liver fibrosis, and NAFLD (Table 1), including that IRF2, 3, 4, 6, and 9 show a protective role in NAFLD, whereas IRF1, 5, 7, and 8 exhibit an accelerated function on NAFLD. In addition, IRFs have been shown to regulate the expression of matrix metalloproteinases (MMPs) in other tissues or organs that play an important role in matrix destruction or degradation [77,78]. Noticeably, the same IRF may function variably in different liver resident cells. Selectively regulating IRF expression may provide therapeutic options for NAFLD and NASH.

4. IRFs in Hepatocellular Carcinoma

IRF1 is known as a tumor suppressor gene in HCC, which can regulate the C–X–C motif chemokine 10 (CXCL10)/chemokine receptor 3 (CXCR3) axis to inhibit tumor cell proliferation, promote cell apoptosis, and induce activation of antitumor immunity [79]. The expression of IRF1 and IRF2 was upregulated in human HCC tumors, which was positively correlated with the expression of programmed death-ligand 1 (PD-L1) [80]. A molecular mechanism study revealed that IRFs can bind the IRF response element in the PD-L1 promoter element to regulate PD-L1 expression. Another study showed that IRF1 accelerated ischemia and reperfusion (I/R) injury after liver transplantation by regulating IL-15 and IL-15 receptor alpha production in hepatocytes [81]. IL-23 has been shown to be upregulated during I/R injury to induce IFN-γ production in natural killer T cells to promote IRF1 expression [82].
The expression of IRF3 in HCC tissues was positively correlated with TLR3 expression, which showed pro-apoptotic activity and served as a good prognostic marker for HCC [83,84]. IRF4 mediated the differentiation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which was also positively correlated with the expression of cellular Myc (c-Myc) in PMN-MDSCs from HCC patients [85]. IRF5 can inhibit hepatitis C virus (HCV)-induced HCC by suppressing HCV replication [86]. Overexpression of IRF8 can significantly improve antitumor effects by increasing anti-PD-1 therapy and regulating the infiltration of tumor-associated macrophages (TAMs) and T-cell function in the HCC tumor microenvironment [87]. The molecular study showed that IRF8 suppressed proto-oncogene c-fos transcription to decrease the expression of CCL20, resulting in a decrease in TAM infiltration [87].
The rs2205986 variant near IRF6 was associated with IFN-β-induced liver injury in patients with multiple sclerosis [88]. IRF7 was downregulated in patients with cytomegalovirus (CMV) infection and late-stage liver fibrosis, compared with that in CMV-negative patients [89]. Hepatitis C virus genotype 3 infection was associated with increased expression of interferon-stimulated genes including IRF9 [31]. However, the roles of IRF6, 7, and 9 in HCC remain to be investigated. Overall, IRFs contribute important roles to the late stage of liver disease (Table 2).

5. Treatment

Early diagnosis of NAFLD and NASH helps for their treatment. Non-pharmacological treatments such as lifestyle and diet modifications are effective for early NAFLD treatment. Drug repurposing has been applied to treat NAFLD. For example, treatment with an antidiatetic drug tofogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to improve glucose metabolism and insulin resistance, ameliorating liver injury [90]. Silymarin, a plant extract from the Silybum marianum with major active component flavonolignans, also shows the potential for NAFLD/NASH therapy [91].
Considering the diverse roles of IRFs in NAFLD and advanced liver disease, selective modulation of their expression may repress or prevent the development of NAFLD and NASH, as well as their associated morbidities. In addition, modulating IRF expression in macrophages can regulate its polarization, which is involved in the pathogenesis of NAFLD and other diseases [51].

5.1. miRNAs

As an epigenetic factor, microRNAs (miRNAs) regulate the expression of genes that participate in the pathogenesis of NAFLD and NASH. Analysis of serum miRNA profiles in patients with simple steatosis or NASH showed that the expression of 23 miRNAs was altered in NASH patients, and 2 miRNAs were changed in patients with steatosis, such as miR-195-5p and miR-16-5p [92]. MiR-23a [93], miR-31 [94], and miR-301a [95] can regulate IRF1 in HCC cells. Treatment of solasonine, a natural component of glycoalkaloid, can upregulate miR-375-3p to suppress IRF5 expression to inhibit human HCC cell line HepG2 growth [96].
MiR-122 as the most abundant microRNA in hepatocytes can downregulate the phosphorylation of STAT3 (signal transducer and activator of transcription 3) that inhibits IFN expression by repressing IRF1 [97]. IL-10 stimulation regulated the expression of miR-146b that targeted IRF5 to regulate macrophage polarization [98].

5.2. PPAR Modulators

It has been shown that IRF-1 mediates the downstream signaling of PPARγ [99,100]. For example, overexpression of PPARγ in vascular smooth muscle cells upregulated the expression of IRF-1, which can be inhibited by PPARγ antagonist GW9662 [100]. PPARγ has been shown to be essential for the inactivation of human HSCs and regression of mouse liver fibrosis [101]. Disruption of PPARγ signaling promoted liver fibrosis and inflammation in CCl4-treated mice, compared with control mice. In addition, knockdown of IRF1/2 in HSCs can upregulate profibrotic genes (Col1α1 and Acta1) and inflammatory genes (IL-6 and IL-1β) expression in HSCs [101]. Therefore, treatment with PPARγ agonist may upregulate IRF1 or IRF2 expression in HSCs to block their activation and fibrogenesis. However, IRF1 and IRF2 showed pro-inflammatory and anti-inflammatory properties in liver macrophages, respectively [15,52,53]. Targeted delivery of drugs is critically important for NASH therapy.

5.3. Anti-Inflammatory and Antioxidant Agents

Plant-derived compounds such as polyphenols with anti-inflammatory activity regulate IRF4 and IRF5 to induce M2-like macrophages and the resolution of inflammation [102]. Anthocyanins, a pigment with antioxidant activity, can downregulate TNF-α-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) via regulating IRF1 and DNA sequence GATA (GATAs), such as GATA-4 and GATA-6 [103]. Phytoestrogens such as genistein, coumestrol, and daidzein, showed similar anti-inflammatory effects as estradiol in LPS treated microglia, macrophages-like cells in the central nervous system [104].

5.4. TLR Agonists or Antagonists

TLRs, a family of pattern recognition receptors (PRRs), interact with pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) to activate the innate immune response, which plays an important role in chronic liver disease [105]. Activation of TLRs occurs in cells that can regulate downstream IRF expression, which contributes to their important roles in inflammation and immune regulation [106,107]. For example, activating TLR3 can enhance the production of IL-6 and IFN-β via modulating NF-κB and IRF signaling pathways, as well as their positive regulator STRAP (serine/threonine kinase receptor-associated protein) [108]. Treatment with an antagonist of TLR7 (immunoregulatory sequence 661) efficiently reduced NASH in mice [34].

5.5. Others

The phosphatase and tensin homolog (PTEN), a tumor suppressor, directly regulates the expression of IRF3 in HCC. Depletion of PTEN in the liver promoted fat accumulation and hepatomegaly by upregulating fatty acid synthesis [109]. Therefore, activation of PTEN/IRF3 signaling in the liver may suppress NAFLD and HCC progression. CRISPR activation plasmid has been shown to modulate the expression of IRF in animal diseases [110]. AAV-8-mediated overexpression of IRF8 can significantly improve anti-PD-1 therapy against HCC [87]. The schematic diagram presented in Figure 3 shows the potential treatments that regulate the expression of IRFs, which might be therapeutic options for NAFLD or NASH.

6. Conclusions

NAFLD is a complex disease with many comorbidities, such as dyslipidemia, obesity, and type 2 diabetes. Without effective treatment, it becomes a leading cause end-stage of liver diseases, including HCC. IRFs, as transcriptional factors, can regulate IFNs, as well as other genes such as HIF-1α, which are associated with the pathogenesis of NAFLD and HCC. Overall, IRF2, 3, 4, 6, and 9 show a protective role in NAFLD, whereas IRF1, 5, 7, and 8 exhibit an accelerated function on NAFLD. In addition, IRFs such as IRF4 and IRF5 are involved in the polarization of macrophages. IRFs have been shown to be regulated by treatments including microRNAs, PPAR modulators, anti-inflammatory agents, and TLR agonists or antagonists. In addition, adenoviruses and CRISPR activation plasmids can be applied to regulate their expression to inhibit their mediated effects. Pre-clinical and clinical trials for evaluating IRF regulators in NAFLD treatment are essential in the future.

Author Contributions

Conceptualization, data curation, writing—original draft preparation, C.Z., S.L. and M.Y.; writing—review and editing, C.Z., S.L. and M.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data supporting this report are included in the paper.

Acknowledgments

Cartoons in Figure 1, Figure 2 and Figure 3 were created with BioRender.com (accessed on 19 April 2022).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Estes, C.; Razavi, H.; Loomba, R.; Younossi, Z.; Sanyal, A.J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 2018, 67, 123–133. [Google Scholar] [CrossRef] [PubMed]
  2. Zheng, Q.; Martin, R.C.; Shi, X.; Pandit, H.; Yu, Y.; Liu, X.; Guo, W.; Tan, M.; Bai, O.; Meng, X.; et al. Lack of FGF21 promotes NASH-HCC transition via hepatocyte-TLR4-IL-17A signaling. Theranostics 2020, 10, 9923–9936. [Google Scholar] [CrossRef] [PubMed]
  3. Hindson, J. Molecular landscape of NASH-HCC. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 456. [Google Scholar] [CrossRef] [PubMed]
  4. Zhang, C.; Yang, M. The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma. Cancers 2021, 13, 3740. [Google Scholar] [CrossRef] [PubMed]
  5. Cholankeril, G.; Patel, R.; Khurana, S.; Satapathy, S.K. Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management. World J. Hepatol. 2017, 9, 533–543. [Google Scholar] [CrossRef] [PubMed]
  6. Jensen, T.; Abdelmalek, M.F.; Sullivan, S.; Nadeau, K.J.; Green, M.; Roncal, C.; Nakagawa, T.; Kuwabara, M.; Sato, Y.; Kang, D.H.; et al. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J. Hepatol. 2018, 68, 1063–1075. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Alwahsh, S.M.; Gebhardt, R. Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD). Arch. Toxicol. 2017, 91, 1545–1563. [Google Scholar] [CrossRef]
  8. Alwahsh, S.M.; Xu, M.; Seyhan, H.A.; Ahmad, S.; Mihm, S.; Ramadori, G.; Schultze, F.C. Diet high in fructose leads to an overexpression of lipocalin-2 in rat fatty liver. World J. Gastroenterol. 2014, 20, 1807–1821. [Google Scholar] [CrossRef]
  9. Zhang, C.; Yang, M. Current Options and Future Directions for NAFLD and NASH Treatment. Int. J. Mol. Sci. 2021, 22, 7571. [Google Scholar] [CrossRef]
  10. Pafili, K.; Roden, M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol. Metab. 2021, 50, 101122. [Google Scholar] [CrossRef]
  11. Yang, M.; Kimchi, E.T.; Staveley-O’Carroll, K.F.; Li, G. Astaxanthin Prevents Diet-Induced NASH Progression by Shaping Intrahepatic Immunity. Int. J. Mol. Sci. 2021, 22, 11037. [Google Scholar] [CrossRef] [PubMed]
  12. Ipsen, D.H.; Lykkesfeldt, J.; Tveden-Nyborg, P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol. Life Sci. 2018, 75, 3313–3327. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Luo, X.Y.; Takahara, T.; Kawai, K.; Fujino, M.; Sugiyama, T.; Tsuneyama, K.; Tsukada, K.; Nakae, S.; Zhong, L.; Li, X.K. IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet. Am. J. Physiol. Gastrointest. Liver Physiol. 2013, 305, G891–G899. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Choi, W.M.; Ryu, T.; Lee, J.H.; Shim, Y.R.; Kim, M.H.; Kim, H.H.; Kim, Y.E.; Yang, K.; Kim, K.; Choi, S.E.; et al. Metabotropic Glutamate Receptor 5 in Natural Killer Cells Attenuates Liver Fibrosis by Exerting Cytotoxicity to Activated Stellate Cells. Hepatology 2021, 74, 2170–2185. [Google Scholar] [CrossRef] [PubMed]
  15. Li, J.; Chen, Q.; Yi, J.; Lan, X.; Lu, K.; Du, X.; Guo, Z.; Guo, Y.; Geng, M.; Li, D.; et al. IFN-γ contributes to the hepatic inflammation in HFD-induced nonalcoholic steatohepatitis by STAT1β/TLR2 signaling pathway. Mol. Immunol. 2021, 134, 118–128. [Google Scholar] [CrossRef]
  16. Wang, J.; Li, H.; Xue, B.; Deng, R.; Huang, X.; Xu, Y.; Chen, S.; Tian, R.; Wang, X.; Xun, Z.; et al. IRF1 Promotes the Innate Immune Response to Viral Infection by Enhancing the Activation of IRF3. J. Virol. 2020, 94, e01231-20. [Google Scholar] [CrossRef]
  17. Zan, J.; Xu, R.; Tang, X.; Lu, M.; Xie, S.; Cai, J.; Huang, Z.; Zhang, J. RNA helicase DDX5 suppresses IFN-I antiviral innate immune response by interacting with PP2A-Cβ to deactivate IRF3. Exp. Cell Res. 2020, 396, 112332. [Google Scholar] [CrossRef]
  18. Taneja, V.; Kalra, P.; Goel, M.; Khilnani, G.C.; Saini, V.; Prasad, G.; Gupta, U.D.; Krishna Prasad, H. Impact and prognosis of the expression of IFN-α among tuberculosis patients. PLoS ONE 2020, 15, e0235488. [Google Scholar] [CrossRef]
  19. Antonczyk, A.; Krist, B.; Sajek, M.; Michalska, A.; Piaszyk-Borychowska, A.; Plens-Galaska, M.; Wesoly, J.; Bluyssen, H.A.R. Direct Inhibition of IRF-Dependent Transcriptional Regulatory Mechanisms Associated With Disease. Front. Immunol. 2019, 10, 1176. [Google Scholar] [CrossRef] [Green Version]
  20. Miyamoto, M.; Fujita, T.; Kimura, Y.; Maruyama, M.; Harada, H.; Sudo, Y.; Miyata, T.; Taniguchi, T. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell 1988, 54, 903–913. [Google Scholar] [CrossRef]
  21. Yanai, H.; Negishi, H.; Taniguchi, T. The IRF family of transcription factors: Inception, impact and implications in oncogenesis. Oncoimmunology 2012, 1, 1376–1386. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Eguchi, J.; Yan, Q.W.; Schones, D.E.; Kamal, M.; Hsu, C.H.; Zhang, M.Q.; Crawford, G.E.; Rosen, E.D. Interferon regulatory factors are transcriptional regulators of adipogenesis. Cell Metab. 2008, 7, 86–94. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Silvestre, M.F.; Kieswich, J.; Yaqoob, M.M.; Holness, M.J.; Sugden, M.C.; Caton, P.W. A key role for interferon regulatory factors in mediating early-life metabolic defects in male offspring of maternal protein restricted rats. Horm. Metab. Res. 2014, 46, 252–258. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Eguchi, J.; Kong, X.; Tenta, M.; Wang, X.; Kang, S.; Rosen, E.D. Interferon regulatory factor 4 regulates obesity-induced inflammation through regulation of adipose tissue macrophage polarization. Diabetes 2013, 62, 3394–3403. [Google Scholar] [CrossRef] [Green Version]
  25. Chen, M.; Wen, X.; Gao, Y.; Liu, B.; Zhong, C.; Nie, J.; Liang, H. IRF-4 deficiency reduces inflammation and kidney fibrosis after folic acid-induced acute kidney injury. Int. Immunopharmacol. 2021, 100, 108142. [Google Scholar] [CrossRef]
  26. Li, Y.; Liu, Y.; Huang, Y.; Yang, K.; Xiao, T.; Xiong, J.; Wang, K.; Liu, C.; He, T.; Yu, Y.; et al. IRF-1 promotes renal fibrosis by downregulation of Klotho. FASEB J. 2020, 34, 4415–4429. [Google Scholar] [CrossRef]
  27. Fabié, A.; Mai, L.T.; Dagenais-Lussier, X.; Hammami, A.; van Grevenynghe, J.; Stäger, S. IRF-5 Promotes Cell Death in CD4 T Cells during Chronic Infection. Cell Rep. 2018, 24, 1163–1175. [Google Scholar] [CrossRef] [Green Version]
  28. Gapud, E.J.; Trejo-Zambrano, M.I.; Gomez-Banuelos, E.; Tiniakou, E.; Antiochos, B.; Granville, D.J.; Andrade, F.; Casciola-Rosen, L.; Rosen, A. Granzyme B Induces IRF-3 Phosphorylation through a Perforin-Independent Proteolysis-Dependent Signaling Cascade without Inducing Cell Death. J. Immunol. 2021, 206, 335–344. [Google Scholar] [CrossRef]
  29. Sun, L.; Li, Y.; Misumi, I.; González-López, O.; Hensley, L.; Cullen, J.M.; McGivern, D.R.; Matsuda, M.; Suzuki, R.; Sen, G.C.; et al. IRF3-mediated pathogenicity in a murine model of human hepatitis A. PLoS Pathog. 2021, 17, e1009960. [Google Scholar] [CrossRef]
  30. Liu, J.; Zhuang, Z.J.; Bian, D.X.; Ma, X.J.; Xun, Y.H.; Yang, W.J.; Luo, Y.; Liu, Y.L.; Jia, L.; Wang, Y.; et al. Toll-like receptor-4 signalling in the progression of non-alcoholic fatty liver disease induced by high-fat and high-fructose diet in mice. Clin. Exp. Pharmacol. Physiol. 2014, 41, 482–488. [Google Scholar] [CrossRef]
  31. Shrivastava, S.; Meissner, E.G.; Funk, E.; Poonia, S.; Shokeen, V.; Thakur, A.; Poonia, B.; Sarin, S.K.; Trehanpati, N.; Kottilil, S. Elevated hepatic lipid and interferon stimulated gene expression in HCV GT3 patients relative to non-alcoholic steatohepatitis. Hepatol. Int. 2016, 10, 937–946. [Google Scholar] [CrossRef] [PubMed]
  32. Klune, J.R.; Dhupar, R.; Kimura, S.; Ueki, S.; Cardinal, J.; Nakao, A.; Nace, G.; Evankovich, J.; Murase, N.; Tsung, A.; et al. Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 303, G666–G673. [Google Scholar] [CrossRef] [PubMed]
  33. Ghazarian, M.; Revelo, X.S.; Nøhr, M.K.; Luck, H.; Zeng, K.; Lei, H.; Tsai, S.; Schroer, S.A.; Park, Y.J.; Chng, M.H.Y.; et al. Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome. Sci. Immunol. 2017, 2, eaai7616. [Google Scholar] [CrossRef] [Green Version]
  34. Roh, Y.S.; Kim, J.W.; Park, S.; Shon, C.; Kim, S.; Eo, S.K.; Kwon, J.K.; Lim, C.W.; Kim, B. Toll-Like Receptor-7 Signaling Promotes Nonalcoholic Steatohepatitis by Inhibiting Regulatory T Cells in Mice. Am. J. Pathol. 2018, 188, 2574–2588. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Quiroga, A.D.; Comanzo, C.G.; Heit Barbini, F.J.; Lucci, A.; Vera, M.C.; Lorenzetti, F.; Ferretti, A.C.; Ceballos, M.P.; Alvarez, M.L.; Carrillo, M.C. IFN-α-2b treatment protects against diet-induced obesity and alleviates non-alcoholic fatty liver disease in mice. Toxicol. Appl. Pharmacol. 2019, 379, 114650. [Google Scholar] [CrossRef]
  36. Sin, W.-X.; Yeong, J.P.-S.; Lim, T.J.F.; Su, I.H.; Connolly, J.E.; Chin, K.-C. IRF-7 Mediates Type I IFN Responses in Endotoxin-Challenged Mice. Front. Immunol. 2020, 11, 640. [Google Scholar] [CrossRef] [Green Version]
  37. Steinhagen, F.; McFarland, A.P.; Rodriguez, L.G.; Tewary, P.; Jarret, A.; Savan, R.; Klinman, D.M. IRF-5 and NF-κB p50 co-regulate IFN-β and IL-6 expression in TLR9-stimulated human plasmacytoid dendritic cells. Eur. J. Immunol. 2013, 43, 1896–1906. [Google Scholar] [CrossRef] [Green Version]
  38. Hart, K.M.; Fabre, T.; Sciurba, J.C.; Gieseck, R.L., 3rd; Borthwick, L.A.; Vannella, K.M.; Acciani, T.H.; de Queiroz Prado, R.; Thompson, R.W.; White, S.; et al. Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-β. Sci. Transl. Med. 2017, 9. [Google Scholar] [CrossRef] [Green Version]
  39. Imanishi, T.; Unno, M.; Kobayashi, W.; Yoneda, N.; Akira, S.; Saito, T. mTORC1 Signaling Controls TLR2-Mediated T-Cell Activation by Inducing TIRAP Expression. Cell Rep. 2020, 32, 107911. [Google Scholar] [CrossRef]
  40. Yan, J.; Pandey, S.P.; Barnes, B.J.; Turner, J.R.; Abraham, C. T Cell-Intrinsic IRF5 Regulates T Cell Signaling, Migration, and Differentiation and Promotes Intestinal Inflammation. Cell Rep. 2020, 31, 107820. [Google Scholar] [CrossRef]
  41. Tarantino, G.; Costantini, S.; Citro, V.; Conforti, P.; Capone, F.; Sorice, A.; Capone, D. Interferon-alpha 2 but not Interferon-gamma serum levels are associated with intramuscular fat in obese patients with nonalcoholic fatty liver disease. J. Transl. Med. 2019, 17, 8. [Google Scholar] [CrossRef] [PubMed]
  42. Aoki, Y.; Sugiyama, M.; Murata, K.; Yoshio, S.; Kurosaki, M.; Hashimoto, S.; Yatsuhashi, H.; Nomura, H.; Kang, J.H.; Takeda, T.; et al. Association of serum IFN-λ3 with inflammatory and fibrosis markers in patients with chronic hepatitis C virus infection. J. Gastroenterol. 2015, 50, 894–902. [Google Scholar] [CrossRef]
  43. Petta, S.; Valenti, L.; Tuttolomondo, A.; Dongiovanni, P.; Pipitone, R.M.; Cammà, C.; Cabibi, D.; Di Marco, V.; Fracanzani, A.L.; Badiali, S.; et al. Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. Hepatology 2017, 66, 1885–1893. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Pelka, K.; Latz, E. IRF5, IRF8, and IRF7 in human pDCs-the good, the bad, and the insignificant? Eur. J. Immunol. 2013, 43, 1693–1697. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Mesev, E.V.; LeDesma, R.A.; Ploss, A. Decoding type I and III interferon signalling during viral infection. Nat. Microbiol. 2019, 4, 914–924. [Google Scholar] [CrossRef] [PubMed]
  46. Michalska, A.; Blaszczyk, K.; Wesoly, J.; Bluyssen, H.A.R. A Positive Feedback Amplifier Circuit That Regulates Interferon (IFN)-Stimulated Gene Expression and Controls Type I and Type II IFN Responses. Front. Immunol. 2018, 9, 1135. [Google Scholar] [CrossRef] [Green Version]
  47. Irving, A.T.; Zhang, Q.; Kong, P.S.; Luko, K.; Rozario, P.; Wen, M.; Zhu, F.; Zhou, P.; Ng, J.H.J.; Sobota, R.M.; et al. Interferon Regulatory Factors IRF1 and IRF7 Directly Regulate Gene Expression in Bats in Response to Viral Infection. Cell Rep. 2020, 33, 108345. [Google Scholar] [CrossRef]
  48. Jefferies, C.A. Regulating IRFs in IFN Driven Disease. Front. Immunol. 2019, 10, 325. [Google Scholar] [CrossRef] [Green Version]
  49. Negishi, H.; Taniguchi, T.; Yanai, H. The Interferon (IFN) Class of Cytokines and the IFN Regulatory Factor (IRF) Transcription Factor Family. Cold Spring Harb. Perspect. Biol. 2018, 10, a028423. [Google Scholar] [CrossRef]
  50. Liu, J.; Cao, S.; Herman, L.M.; Ma, X. Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-gamma-primed IL-12 production by IFN regulatory factor 1. J. Exp. Med. 2003, 198, 1265–1276. [Google Scholar] [CrossRef] [Green Version]
  51. Zhang, C.; Yang, M.; Ericsson, A.C. Function of Macrophages in Disease: Current Understanding on Molecular Mechanisms. Front. Immunol. 2021, 12, 620510. [Google Scholar] [CrossRef] [PubMed]
  52. Seidman, J.S.; Troutman, T.D.; Sakai, M.; Gola, A.; Spann, N.J.; Bennett, H.; Bruni, C.M.; Ouyang, Z.; Li, R.Z.; Sun, X.; et al. Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis. Immunity 2020, 52, 1057–1074.e7. [Google Scholar] [CrossRef]
  53. Cui, H.; Banerjee, S.; Guo, S.; Xie, N.; Liu, G. IFN Regulatory Factor 2 Inhibits Expression of Glycolytic Genes and Lipopolysaccharide-Induced Proinflammatory Responses in Macrophages. J. Immunol. 2018, 200, 3218–3230. [Google Scholar] [CrossRef] [PubMed]
  54. Fang, J.; Ji, Y.X.; Zhang, P.; Cheng, L.; Chen, Y.; Chen, J.; Su, Y.; Cheng, X.; Zhang, Y.; Li, T.; et al. Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3. Hepatology 2020, 71, 1592–1608. [Google Scholar] [CrossRef] [PubMed]
  55. Wang, X.A.; Zhang, R.; She, Z.G.; Zhang, X.F.; Jiang, D.S.; Wang, T.; Gao, L.; Deng, W.; Zhang, S.M.; Zhu, L.H.; et al. Interferon regulatory factor 3 constrains IKKβ/NF-κB signaling to alleviate hepatic steatosis and insulin resistance. Hepatology 2014, 59, 870–885. [Google Scholar] [CrossRef]
  56. Benzler, J.; Ganjam, G.K.; Pretz, D.; Oelkrug, R.; Koch, C.E.; Legler, K.; Stöhr, S.; Culmsee, C.; Williams, L.M.; Tups, A. Central inhibition of IKKβ/NF-κB signaling attenuates high-fat diet-induced obesity and glucose intolerance. Diabetes 2015, 64, 2015–2027. [Google Scholar] [CrossRef] [Green Version]
  57. Hernandez, R.; Zhou, C. Recent Advances in Understanding the Role of IKKβ in Cardiometabolic Diseases. Front. Cardiovasc. Med. 2021, 8, 752337. [Google Scholar] [CrossRef]
  58. Douglass, J.D.; Dorfman, M.D.; Fasnacht, R.; Shaffer, L.D.; Thaler, J.P. Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation. Mol. Metab. 2017, 6, 366–373. [Google Scholar] [CrossRef]
  59. Ni, Y.; Zhuge, F.; Nagashimada, M.; Ota, T. Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis. Nutrients 2016, 8, 391. [Google Scholar] [CrossRef] [Green Version]
  60. Huang, S.C.; Smith, A.M.; Everts, B.; Colonna, M.; Pearce, E.L.; Schilling, J.D.; Pearce, E.J. Metabolic Reprogramming Mediated by the mTORC2-IRF4 Signaling Axis Is Essential for Macrophage Alternative Activation. Immunity 2016, 45, 817–830. [Google Scholar] [CrossRef] [Green Version]
  61. Vasanthakumar, A.; Moro, K.; Xin, A.; Liao, Y.; Gloury, R.; Kawamoto, S.; Fagarasan, S.; Mielke, L.A.; Afshar-Sterle, S.; Masters, S.L.; et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat. Immunol. 2015, 16, 276–285. [Google Scholar] [CrossRef] [PubMed]
  62. Fabrizi, M.; Marchetti, V.; Mavilio, M.; Marino, A.; Casagrande, V.; Cavalera, M.; Moreno-Navarrete, J.M.; Mezza, T.; Sorice, G.P.; Fiorentino, L.; et al. IL-21 is a major negative regulator of IRF4-dependent lipolysis affecting Tregs in adipose tissue and systemic insulin sensitivity. Diabetes 2014, 63, 2086–2096. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Sindhu, S.; Kochumon, S.; Thomas, R.; Bennakhi, A.; Al-Mulla, F.; Ahmad, R. Enhanced Adipose Expression of Interferon Regulatory Factor (IRF)-5 Associates with the Signatures of Metabolic Inflammation in Diabetic Obese Patients. Cells 2020, 9, 730. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Alzaid, F.; Lagadec, F.; Albuquerque, M.; Ballaire, R.; Orliaguet, L.; Hainault, I.; Blugeon, C.; Lemoine, S.; Lehuen, A.; Saliba, D.G.; et al. IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans. JCI Insight 2016, 1, e88689. [Google Scholar] [CrossRef] [Green Version]
  65. Krausgruber, T.; Blazek, K.; Smallie, T.; Alzabin, S.; Lockstone, H.; Sahgal, N.; Hussell, T.; Feldmann, M.; Udalova, I.A. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat. Immunol. 2011, 12, 231–238. [Google Scholar] [CrossRef]
  66. Dalmas, E.; Toubal, A.; Alzaid, F.; Blazek, K.; Eames, H.L.; Lebozec, K.; Pini, M.; Hainault, I.; Montastier, E.; Denis, R.G.; et al. Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat. Med. 2015, 21, 610–618. [Google Scholar] [CrossRef]
  67. Tong, J.; Han, C.J.; Zhang, J.Z.; He, W.Z.; Zhao, G.J.; Cheng, X.; Zhang, L.; Deng, K.Q.; Liu, Y.; Fan, H.F.; et al. Hepatic Interferon Regulatory Factor 6 Alleviates Liver Steatosis and Metabolic Disorder by Transcriptionally Suppressing Peroxisome Proliferator-Activated Receptor γ in Mice. Hepatology 2019, 69, 2471–2488. [Google Scholar] [CrossRef]
  68. Wang, X.A.; Zhang, R.; Zhang, S.; Deng, S.; Jiang, D.; Zhong, J.; Yang, L.; Wang, T.; Hong, S.; Guo, S.; et al. Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 2013, 305, E485–E495. [Google Scholar] [CrossRef] [Green Version]
  69. Kawai, T.; Sato, S.; Ishii, K.J.; Coban, C.; Hemmi, H.; Yamamoto, M.; Terai, K.; Matsuda, M.; Inoue, J.; Uematsu, S.; et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 2004, 5, 1061–1068. [Google Scholar] [CrossRef]
  70. Salem, S.; Salem, D.; Gros, P. Role of IRF8 in immune cells functions, protection against infections, and susceptibility to inflammatory diseases. Hum. Genet. 2020, 139, 707–721. [Google Scholar] [CrossRef]
  71. Langlais, D.; Barreiro, L.B.; Gros, P. The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation. J. Exp. Med. 2016, 213, 585–603. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Berghout, J.; Langlais, D.; Radovanovic, I.; Tam, M.; MacMicking, J.D.; Stevenson, M.M.; Gros, P. Irf8-regulated genomic responses drive pathological inflammation during cerebral malaria. PLoS Pathog. 2013, 9, e1003491. [Google Scholar] [CrossRef] [PubMed]
  73. Shiau, C.E.; Kaufman, Z.; Meireles, A.M.; Talbot, W.S. Differential requirement for irf8 in formation of embryonic and adult macrophages in zebrafish. PLoS ONE 2015, 10, e0117513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Yang, Q.; Yan, C.; Gong, Z. Interaction of hepatic stellate cells with neutrophils and macrophages in the liver following oncogenic kras activation in transgenic zebrafish. Sci. Rep. 2018, 8, 8495. [Google Scholar] [CrossRef]
  75. Xu, H.; Zhu, J.; Smith, S.; Foldi, J.; Zhao, B.; Chung, A.Y.; Outtz, H.; Kitajewski, J.; Shi, C.; Weber, S.; et al. Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat. Immunol. 2012, 13, 642–650. [Google Scholar] [CrossRef] [Green Version]
  76. Wang, X.A.; Zhang, R.; Jiang, D.; Deng, W.; Zhang, S.; Deng, S.; Zhong, J.; Wang, T.; Zhu, L.H.; Yang, L.; et al. Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice. Hepatology 2013, 58, 603–616. [Google Scholar] [CrossRef] [Green Version]
  77. Yang, Q.; Ding, W.; Cao, Y.; Zhou, Y.; Ni, S.; Shi, T.; Fu, W. Interferonregulatoryfactor-8(IRF-8) regulates the expression of matrix metalloproteinase-13 (MMP-13) in chondrocytes. Cell Stress Chaperones 2018, 23, 393–398. [Google Scholar] [CrossRef]
  78. Chen, Y.J.; Liang, L.; Li, J.; Wu, H.; Dong, L.; Liu, T.T.; Shen, X.Z. IRF-2 Inhibits Gastric Cancer Invasion and Migration by Down-Regulating MMP-1. Dig. Dis. Sci. 2020, 65, 168–177. [Google Scholar] [CrossRef]
  79. Yan, Y.; Zheng, L.; Du, Q.; Yazdani, H.; Dong, K.; Guo, Y.; Geller, D.A. Interferon regulatory factor 1(IRF-1) activates anti-tumor immunity via CXCL10/CXCR3 axis in hepatocellular carcinoma (HCC). Cancer Lett. 2021, 506, 95–106. [Google Scholar] [CrossRef]
  80. Yan, Y.; Zheng, L.; Du, Q.; Yan, B.; Geller, D.A. Interferon regulatory factor 1 (IRF-1) and IRF-2 regulate PD-L1 expression in hepatocellular carcinoma (HCC) cells. Cancer Immunol. Immunother. 2020, 69, 1891–1903. [Google Scholar] [CrossRef]
  81. Yokota, S.; Yoshida, O.; Dou, L.; Spadaro, A.V.; Isse, K.; Ross, M.A.; Stolz, D.B.; Kimura, S.; Du, Q.; Demetris, A.J.; et al. IRF-1 promotes liver transplant ischemia/reperfusion injury via hepatocyte IL-15/IL-15Rα production. J. Immunol. 2015, 194, 6045–6056. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Klune, J.R.; Bartels, C.; Luo, J.; Yokota, S.; Du, Q.; Geller, D.A. IL-23 mediates murine liver transplantation ischemia-reperfusion injury via IFN-γ/IRF-1 pathway. Am. J. Physiol. Gastrointest. Liver Physiol. 2018, 315, G991–G1002. [Google Scholar] [CrossRef] [PubMed]
  83. Yuan, M.M.; Xu, Y.Y.; Chen, L.; Li, X.Y.; Qin, J.; Shen, Y. TLR3 expression correlates with apoptosis, proliferation and angiogenesis in hepatocellular carcinoma and predicts prognosis. BMC Cancer 2015, 15, 245. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Yoneda, K.; Sugimoto, K.; Shiraki, K.; Tanaka, J.; Beppu, T.; Fuke, H.; Yamamoto, N.; Masuya, M.; Horie, R.; Uchida, K.; et al. Dual topology of functional Toll-like receptor 3 expression in human hepatocellular carcinoma: Differential signaling mechanisms of TLR3-induced NF-kappaB activation and apoptosis. Int. J. Oncol. 2008, 33, 929–936. [Google Scholar]
  85. Yang, Q.; Xie, H.; Li, X.; Feng, Y.; Xie, S.; Qu, J.; Xie, A.; Zhu, Y.; Zhou, L.; Yang, J.; et al. Interferon Regulatory Factor 4 Regulates the Development of Polymorphonuclear Myeloid-Derived Suppressor Cells Through the Transcription of c-Myc in Cancer. Front. Immunol. 2021, 12, 627072. [Google Scholar] [CrossRef]
  86. Cevik, O.; Li, D.; Baljinnyam, E.; Manvar, D.; Pimenta, E.M.; Waris, G.; Barnes, B.J.; Kaushik-Basu, N. Interferon regulatory factor 5 (IRF5) suppresses hepatitis C virus (HCV) replication and HCV-associated hepatocellular carcinoma. J. Biol. Chem. 2017, 292, 21676–21689. [Google Scholar] [CrossRef] [Green Version]
  87. Wu, H.; Li, Y.; Shi, G.; Du, S.; Wang, X.; Ye, W.; Zhang, Z.; Chu, Y.; Ma, S.; Wang, D.; et al. Hepatic interferon regulatory factor 8 expression suppresses hepatocellular carcinoma progression and enhances the response to anti-programmed cell death protein-1 therapy. Hepatology 2022. [Google Scholar] [CrossRef]
  88. Kowalec, K.; Wright, G.E.B.; Drögemöller, B.I.; Aminkeng, F.; Bhavsar, A.P.; Kingwell, E.; Yoshida, E.M.; Traboulsee, A.; Marrie, R.A.; Kremenchutzky, M.; et al. Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis. Nat. Genet. 2018, 50, 1081–1085. [Google Scholar] [CrossRef]
  89. Ibrahim, M.K.; Khedr, A.; Bader El Din, N.G.; Khairy, A.; El Awady, M.K. Increased incidence of cytomegalovirus coinfection in HCV-infected patients with late liver fibrosis is associated with dysregulation of JAK-STAT pathway. Sci. Rep. 2017, 7, 10364. [Google Scholar] [CrossRef] [Green Version]
  90. Goya, T.; Imoto, K.; Tashiro, S.; Aoyagi, T.; Takahashi, M.; Kurokawa, M.; Suzuki, H.; Tanaka, M.; Kato, M.; Kohjima, M.; et al. The Efficacy of Tofogliflozin on Metabolic Dysfunction-Associated Fatty Liver Disease. Gastroenterol. Insights 2022, 13, 3. [Google Scholar] [CrossRef]
  91. Hashem, A.; Shastri, Y.; Al Otaibi, M.; Buchel, E.; Saleh, H.; Ahmad, R.; Ahmed, H.; Al Idris, F.; Ahmed, S.; Guda, M.; et al. Expert Opinion on the Management of Non-Alcoholic Fatty Liver Disease (NAFLD) in the Middle East with a Focus on the Use of Silymarin. Gastroenterol. Insights 2021, 12, 14. [Google Scholar] [CrossRef]
  92. Vulf, M.; Shunkina, D.; Komar, A.; Bograya, M.; Zatolokin, P.; Kirienkova, E.; Gazatova, N.; Kozlov, I.; Litvinova, L. Analysis of miRNAs Profiles in Serum of Patients With Steatosis and Steatohepatitis. Front. Cell Dev. Biol. 2021, 9, 736677. [Google Scholar] [CrossRef] [PubMed]
  93. Yan, Y.; Liang, Z.; Du, Q.; Yang, M.; Geller, D.A. MicroRNA-23a downregulates the expression of interferon regulatory factor-1 in hepatocellular carcinoma cells. Oncol. Rep. 2016, 36, 633–640. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Wan, P.Q.; Zhang, J.H.; Du, Q.; Dong, K.; Luo, J.; Heres, C.; Geller, D.A. Analysis of the relationship between microRNA-31 and interferon regulatory factor-1 in hepatocellular carcinoma cells. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 647–654. [Google Scholar] [CrossRef]
  95. Dong, K.; Du, Q.; Cui, X.; Wan, P.; Kaltenmeier, C.; Luo, J.; Yan, B.; Yan, Y.; Geller, D.A. MicroRNA-301a (miR-301a) is induced in hepatocellular carcinoma (HCC) and down- regulates the expression of interferon regulatory factor-1. Biochem. Biophys. Res. Commun. 2020, 524, 273–279. [Google Scholar] [CrossRef]
  96. Liu, Z.; Ma, C.; Tang, X.; Tang, Q.; Lou, L.; Yu, Y.; Zheng, F.; Wu, J.; Yang, X.B.; Wang, W.; et al. The Reciprocal Interaction Between LncRNA CCAT1 and miR-375-3p Contribute to the Downregulation of IRF5 Gene Expression by Solasonine in HepG2 Human Hepatocellular Carcinoma Cells. Front. Oncol. 2019, 9, 1081. [Google Scholar] [CrossRef] [Green Version]
  97. Xu, H.; Xu, S.J.; Xie, S.J.; Zhang, Y.; Yang, J.H.; Zhang, W.Q.; Zheng, M.N.; Zhou, H.; Qu, L.H. MicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway. eLife 2019, 8, 41159. [Google Scholar] [CrossRef]
  98. Peng, L.; Zhang, H.; Hao, Y.; Xu, F.; Yang, J.; Zhang, R.; Lu, G.; Zheng, Z.; Cui, M.; Qi, C.F.; et al. Reprogramming macrophage orientation by microRNA 146b targeting transcription factor IRF5. EBioMedicine 2016, 14, 83–96. [Google Scholar] [CrossRef] [Green Version]
  99. Varley, C.L.; Bacon, E.J.; Holder, J.C.; Southgate, J. FOXA1 and IRF-1 intermediary transcriptional regulators of PPARgamma-induced urothelial cytodifferentiation. Cell Death Differ. 2009, 16, 103–114. [Google Scholar] [CrossRef] [Green Version]
  100. Lin, Y.; Zhu, X.; McLntee, F.L.; Xiao, H.; Zhang, J.; Fu, M.; Chen, Y.E. Interferon regulatory factor-1 mediates PPARgamma-induced apoptosis in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 2004, 24, 257–263. [Google Scholar] [CrossRef] [Green Version]
  101. Liu, X.; Xu, J.; Rosenthal, S.; Zhang, L.-J.; McCubbin, R.; Meshgin, N.; Shang, L.; Koyama, Y.; Ma, H.-Y.; Sharma, S.; et al. Identification of Lineage-Specific Transcription Factors That Prevent Activation of Hepatic Stellate Cells and Promote Fibrosis Resolution. Gastroenterology 2020, 158, 1728–1744.e14. [Google Scholar] [CrossRef] [Green Version]
  102. Merecz-Sadowska, A.; Sitarek, P.; Śliwiński, T.; Zajdel, R. Anti-Inflammatory Activity of Extracts and Pure Compounds Derived from Plants via Modulation of Signaling Pathways, Especially PI3K/AKT in Macrophages. Int. J. Mol. Sci. 2020, 21, 9605. [Google Scholar] [CrossRef] [PubMed]
  103. Nizamutdinova, I.T.; Kim, Y.M.; Chung, J.I.; Shin, S.C.; Jeong, Y.K.; Seo, H.G.; Lee, J.H.; Chang, K.C.; Kim, H.J. Anthocyanins from black soybean seed coats preferentially inhibit TNF-alpha-mediated induction of VCAM-1 over ICAM-1 through the regulation of GATAs and IRF-1. J. Agric. Food Chem. 2009, 57, 7324–7330. [Google Scholar] [CrossRef]
  104. Jantaratnotai, N.; Utaisincharoen, P.; Sanvarinda, P.; Thampithak, A.; Sanvarinda, Y. Phytoestrogens mediated anti-inflammatory effect through suppression of IRF-1 and pSTAT1 expressions in lipopolysaccharide-activated microglia. Int. Immunopharmacol. 2013, 17, 483–488. [Google Scholar] [CrossRef]
  105. Zhang, C.; Yang, M.; Ericsson, A.C. The Potential Gut Microbiota-Mediated Treatment Options for Liver Cancer. Front. Oncol. 2020, 10, 524205. [Google Scholar] [CrossRef]
  106. Bender, A.T.; Tzvetkov, E.; Pereira, A.; Wu, Y.; Kasar, S.; Przetak, M.M.; Vlach, J.; Niewold, T.B.; Jensen, M.A.; Okitsu, S.L. TLR7 and TLR8 Differentially Activate the IRF and NF-κB Pathways in Specific Cell Types to Promote Inflammation. Immunohorizons 2020, 4, 93–107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Bhatelia, K.; Singh, K.; Singh, R. TLRs: Linking inflammation and breast cancer. Cell. Signal. 2014, 26, 2350–2357. [Google Scholar] [CrossRef]
  108. Huh, H.D.; Lee, E.; Shin, J.; Park, B.; Lee, S. STRAP positively regulates TLR3-triggered signaling pathway. Cell. Immunol. 2017, 318, 55–60. [Google Scholar] [CrossRef] [PubMed]
  109. Stiles, B.; Wang, Y.; Stahl, A.; Bassilian, S.; Lee, W.P.; Kim, Y.J.; Sherwin, R.; Devaskar, S.; Lesche, R.; Magnuson, M.A.; et al. Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc. Natl. Acad. Sci. USA 2004, 101, 2082–2087. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Dai, J.; Xu, S.; Okada, T.; Liu, Y.; Zuo, G.; Tang, J.; Zhang, J.H.; Shi, H. T0901317, an Agonist of Liver X Receptors, Attenuates Neuronal Apoptosis in Early Brain Injury after Subarachnoid Hemorrhage in Rats via Liver X Receptors/Interferon Regulatory Factor/P53 Upregulated Modulator of Apoptosis/Dynamin-1-Like Protein Pathway. Oxid. Med. Cell Longev. 2021, 2021, 8849131. [Google Scholar] [CrossRef]
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Figure 1. Toll-like receptor-mediated signaling pathways of interferon (IFN) transcription. Modulation of TLRs such as TLR2, TLR4, and TLR9 can activate downstream MyD88/NF-κB, MyD88/TRAF6/3/IRF, or TRIF/IRF3/7 signaling pathways to regulate the transcription of type I, II, and III IFNs. TRAF: tumor necrosis factor receptor-associated factor.
Figure 1. Toll-like receptor-mediated signaling pathways of interferon (IFN) transcription. Modulation of TLRs such as TLR2, TLR4, and TLR9 can activate downstream MyD88/NF-κB, MyD88/TRAF6/3/IRF, or TRIF/IRF3/7 signaling pathways to regulate the transcription of type I, II, and III IFNs. TRAF: tumor necrosis factor receptor-associated factor.
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Figure 2. IRFs regulate macrophage polarization. The expression of IRF1 in macrophages can be induced by IFN-γ, synergizing with nuclear factor kappa B (NF-κB) to induce IL-12, inducible nitric oxide synthase (iNOS), and IFN-β production (M1-like macrophages), whereas IL-4 can induce M2-like macrophage polarization by activating IRF4 signaling to prevent IRF5-mediated M1 polarization.
Figure 2. IRFs regulate macrophage polarization. The expression of IRF1 in macrophages can be induced by IFN-γ, synergizing with nuclear factor kappa B (NF-κB) to induce IL-12, inducible nitric oxide synthase (iNOS), and IFN-β production (M1-like macrophages), whereas IL-4 can induce M2-like macrophage polarization by activating IRF4 signaling to prevent IRF5-mediated M1 polarization.
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Figure 3. Treatment options for NASH by regulating IRFs. Up- or downregulating IRFs by TLR agonists or antagonists, PPAR modulators, specific antibodies, adenoviruses-mediated therapy, CRISPR edition, miRNAs, and anti-inflammatory and antioxidant agents can suppress the development of NAFLD or NASH.
Figure 3. Treatment options for NASH by regulating IRFs. Up- or downregulating IRFs by TLR agonists or antagonists, PPAR modulators, specific antibodies, adenoviruses-mediated therapy, CRISPR edition, miRNAs, and anti-inflammatory and antioxidant agents can suppress the development of NAFLD or NASH.
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Table
Table 1. The role of IRFs in NAFLD and NASH.
Table 1. The role of IRFs in NAFLD and NASH.
IRFsModelExpression *FunctionReferences
IRF1NASH ratIncreasedIFN-γ in rat NASH liver upregulated IRF1 expression, resulting in liver inflammation progression.[15]
IRF2M1-like macrophagesDecreasedKnockdown of IRF2 accelerated lipopolysaccharide (LPS)-induced activation of macrophages by regulating hypoxia-inducible factor 1-alpha (HIF-1α)-dependent glycolysis.[53]
IRF3NAFLD miceDecreasedIRF3 deficiency dramatically promoted diet-induced hepatic steatosis, and insulin resistance, whereas overexpression of IRF3 induced hemostasis of glucose and lipid balance metabolism, via regulating nuclear factor-kappa B kinase subunit beta (IKKβ)/nuclear factor kappa B (NF-κB) signaling pathway.[55]
IRF4M2-like macrophagesIncreasedIRF4 is involved in M2-like macrophage polarization induced by IL-4 or mediated by the mTORC2 signaling pathway.[59,60]
IRF5Mice with liver fibrosisIncreasedMice with IRF5 knockdown in myeloid cells were protected from metabolic stress or toxin-induced liver fibrosis, compared with wild-type controls.[64]
IRF6NAFLD miceDecreasedCellular mechanism study showed that knockout IRF6 specifically in hepatocytes accelerated liver steatosis, while overexpression of IRF6 in hepatocytes ameliorated liver steatosis.[67]
IRF7Obese miceIncreasedIRF7 deficiency reduced body weight, insulin resistance, hepatic macrophage infiltration, inflammation, and steatosis in mice on a high-fat diet (HFD).[68]
IRF8Zebrafish with liver fibrosisIncreasedKnocking down IRF8 in zebrafish caused a reduction in macrophage numbers and the number and activation of hepatic stellate cells.[73,74]
IRF9Obese miceDecreasedIRF9 knockout increased insulin resistance, hepatic steatosis, inflammation in mice on HFD.[76]
* The increase or decrease in IRF denotes its expression during the progression of NAFLD, liver fibrosis, and macrophage polarization.
Table
Table 2. The role of IRFs in advanced liver disease.
Table 2. The role of IRFs in advanced liver disease.
IRFsDiseaseExpressionFunctionReferences
IRF1HCCUpregulatedIRF1 was upregulated in mouse and human HCC cells treated with IFN-γ to upregulate PD-L1 expression.[80]
IRF2HCCUpregulatedIRF2 was positively associated with IRF1 and PD-L1 expression in HCC.[80]
IRF3HCCDecreasedThe expression of IRF3 in HCC tissues was positively correlated with TLR3 expression.[83]
IRF4HCCUpregulatedIRF4 mediated differentiation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in human HCC tumor tissues.[85]
IRF5HCCDecreasedIRF5 can inhibit hepatitis C virus (HCV)-induced HCC by suppressing HCV replication.[86]
IRF6Liver injury in patients with multiple sclerosisMutationThe rs2205986 variant near IRF6 was associated with IFN-β-induced liver injury in patients with multiple sclerosis.[88]
IRF7Viral infection-induced liver fibrosisDecreasedIRF7 was downregulated in patients with cytomegalovirus (CMV) infection and late fibrosis, compared with that in CMV-negative patients.[89]
IRF8HCCDecreasedOverexpression of IRF8 can significantly improve antitumor effects by increasing an-ti-PD-1 therapy and regulating the infiltration of tumor-associated macrophages (TAMs) and T-cell function in the HCC tumor microenvironment.[87]
IRF9Hepatitis C virus genotype 3 infectionIncreasedHepatitis C virus genotype 3 infection was associated with increased expression of interferon-stimulated genes including IRF9.[31]
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Zhang, C.; Liu, S.; Yang, M. The Role of Interferon Regulatory Factors in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. Gastroenterol. Insights 2022, 13, 148-161. https://doi.org/10.3390/gastroent13020016

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Zhang C, Liu S, Yang M. The Role of Interferon Regulatory Factors in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. Gastroenterology Insights. 2022; 13(2):148-161. https://doi.org/10.3390/gastroent13020016

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Zhang, Chunye, Shuai Liu, and Ming Yang. 2022. "The Role of Interferon Regulatory Factors in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis" Gastroenterology Insights 13, no. 2: 148-161. https://doi.org/10.3390/gastroent13020016

APA Style

Zhang, C., Liu, S., & Yang, M. (2022). The Role of Interferon Regulatory Factors in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. Gastroenterology Insights, 13(2), 148-161. https://doi.org/10.3390/gastroent13020016

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