Adipose tissue fibrosis, characterized by abnormal extracellular matrix deposition within adipose tissue, signifies a crucial indicator of adipose tissue malfunction, potentially leading to organ tissue dysfunction. Various factors, including a high-fat diet, non-alcoholic fatty liver disease, and insulin resistance, coincide with adipose tissue fibrosis. MicroRNAs (miRNAs) represent a class of small non-coding RNAs with significant influence on tissue fibrosis through diverse signaling pathways. For instance, in response to a high-fat diet, miRNAs can modulate signaling pathways such as TGF-β/Smad, PI3K/AKT, and PPAR-γ to impact adipose tissue fibrosis. Furthermore, miRNAs play roles in inhibiting fibrosis in different contexts: suppressing corneal fibrosis via the TGF-β/Smad pathway, mitigating cardiac fibrosis through the VEGF signaling pathway, reducing wound fibrosis via regulation of the MAPK signaling pathway, and diminishing fibrosis post-fat transplantation via involvement in the PDGFR-β signaling pathway. Notably, the secretome released by miRNA-transfected adipose-derived stem cells facilitates targeted delivery of miRNAs to evade host immune rejection, enhancing their anti-fibrotic efficacy. Hence, this study endeavors to elucidate the role and mechanism of miRNAs in adipose tissue fibrosis and explore the mechanisms and advantages of the secretome released by miRNA-transfected adipose-derived stem cells in combating fibrotic diseases.

Pien Tze Huang (PTH), a well-established traditional Chinese medicine compound, has exhibited anti-hepatic fibrosis properties both in vitro and in vivo animal models, but the randomized clinical trials to evaluate anti-hepatic fibrosis efficacy of PTH are deficient. Chronic hepatitis B (CHB) is a leading cause of hepatic fibrosis in China. Although antiviral therapies have demonstrated significant effectiveness in arresting the progression of fibrotic disease, complete regression of established fibrosis is limited to only a subset of treated patients.

To assess the efficacy of PTH in improving hepatic fibrosis in CHB patients.

We conducted a randomized, double-blind, placebo-controlled clinical trial involving 144 CHB patients with hepatic fibrosis. This study was carried out from September 2020 to April 2023. (Clinical Trials Registration: ChiCTR2000035128) METHODS: CHB patients with an Ishak score of 2-5 points were recruited from ten hospitals across China. Participants were randomized in 1:1 ratio to receive either oral PTH (0.6 g per dose, three times/day) or placebo for 48 weeks, in addition to the standard treatment of entecavir (0.5 mg/day). The primary endpoint was the change in Ishak score. Secondary outcomes included changes in Knodell HAI score, liver stiffness measurement, AST- to -platelet ratio index, Fibrosis-4 index and hepatic function indices.

Of the 144 randomized patients, 142 patients (71 in the PTH group and 71 in the placebo group) were included in the primary analysis. The PTH group exhibited lower Ishak score compared to the control group (2.37 ± 0.94 vs. 2.87 ± 1.04, F = 6.072, p = 0.015). Notably, in treatment-naive patients, the PTH group showed significant improvement in Ishak score post-treatment compared with the control group (2.13 ± 0.72 vs. 2.74 ± 1.07, F = 6.336, p = 0.014). However, no significant changes were observed in these parameters among patients already receiving antiviral therapy.

The combination of PTH and entecavir demonstrates significant improvement in hepatic fibrosis among CHB patients, especially those who are treatment-naive patients.

Liver fibrosis is a crucial condition for evaluating the prognosis of chronic liver disease. Lectin-1ike oxidized low density lipoprotein receptor-1 (LOX-1) has been shown potential research value and therapeutic targeting possibilities in different fibrotic diseases. However, the role of LOX-1 and the underlying mechanisms in liver fibrosis progression remain unclear.

LOX-1 expression was detected in liver tissues from patients and rodents with liver fibrosis. LOX-1 knockout rats were subjected to CCl4 or methionine and choline-deficient diet (MCD) to induce liver fibrosis. Transcriptomic and metabolomics analysis were used to investigate the involvement and mechanism of LOX-1 on liver fibrosis.

We found that LOX-1 exacerbated liver fibrosis by promoting hepatic stellate cells (HSCs) activation. LOX-1 deletion reversed the development of liver fibrosis. We further verified that LOX-1 drove liver fibrosis by reprogramming glutamine metabolism through mediating isoform switching of glutaminase (GLS). Mechanistically, we revealed the crucial role of the LOX-1/OCT1/GLS1 axis in the pathogenesis of liver fibrosis. Moreover, LOX-1 rewired ammonia metabolism by regulating glutamine metabolism-urea cycle to drive the progression of liver fibrosis.

Our findings uncover the pivotal role of LOX-1 in the progression of liver fibrosis, enrich the pathological significance of LOX-1 regulation of hepatic ammonia metabolism, and provide an insight into promising targets for the therapeutic strategy of liver fibrosis, demonstrating the potential clinical value of targeting LOX-1 in antifibrotic therapy.

Dysregulated metabolism of immune cells in the tumor microenvironment leads to immune evasion and tumor progression. As a major cell component in the tumor, the metabolic reprogramming of tumor-associated macrophages (TAMs) creates an immunosuppressive microenvironment in hepatocellular carcinoma (HCC). Our study found that sphingolipid (particularly, sphingosine-1-phosphate or S1P) levels are a clinical indicator for prognosis and immunotherapy response in patients with HCC. S1P primarily derived from TAMs, where NIMA-related kinase 2 (NEK2) plays a key role in controlling the activity of serine palmitoyl-CoA transferase, a rate-limiting enzyme in S1P biosynthesis. The S1P produced by NEK2hi TAMs promotes hepatic tumor progression and confers immunotherapy resistance. Targeting S1P synthesis with a NEK2 inhibitor or S1P antagonist disrupted the immunosuppressive function of macrophages, shifted regulatory T cells (Tregs) to TH17 cells, and increased the number and activity of tumor-infiltrating T effectors, thereby enhancing antitumor efficacy in synergy with immune checkpoint blockade therapy.

Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM), primarily produced by activated hepatic stellate cells (HSCs). The activation of HSCs is influenced by paracrine signaling interactions among various liver cell types, but molecular mechanisms remain to be elucidated. Secretory Meteorin-like (Metrnl) can effectively ameliorate fulminant hepatitis. However, little is known about its role in liver fibrosis. In our study, we found that hepatic Metrnl mRNA transcripts and protein expression were significantly downregulated in patients and mouse models of hepatic fibrosis. Hepatocyte-specific and global knockout of Metrnl exacerbated CCl4-induced liver fibrosis. In contrast, the administration recombinant Metrnl or AAV-Metrnl overexpression markedly ameliorated CCl4-induced liver fibrosis in mice, suggesting a protective role for Metrnl. Mechanistically, hepatocyte-derived Metrnl not only influences the activation of HSCs through paracrine signaling but also modulates the release of the fibrogenic cytokine PDGFB via the transcription factor EGR1, thereby regulating PDGFB/PDGFRβ signaling to affect HSC activation. Furthermore, Metrnl absence in hepatocytes and HSCs leads to the downregulation of the E3 ubiquitin ligase HECW2, inhibiting K48-linked ubiquitination of FN and preventing its proteasomal degradation, thus promoting FN secretion from HSCs. These effects contribute to ECM deposition and the activation of HSCs, ultimately exacerbating liver fibrosis. Collectively, our study reveals Metrnl as a novel regulator of liver fibrosis that mediates communication between hepatocytes and HSCs, indicating its potential as a therapeutic target for liver fibrosis. The identification of Metrnl as a critical player in the pathogenesis of hepatic fibrosis underscores the importance of understanding cellular crosstalk in the progression of liver disease.

Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) may have hepatic benefits in patients with primarily chronic liver disease. ACE-I/ARB have not been evaluated in broad cohorts inclusive of those with decompensated cirrhosis. We analyzed the real-world association between ACE-I/ARB exposure and cirrhosis-related outcomes in a national cohort.

We performed a retrospective, active comparator new user study of patients with cirrhosis in the Veterans Health Administration. We identified new initiators of ACE-I/ARB or calcium channel blockers (comparator). Inverse probability treatment weighting balanced key confounders and Cox regression evaluated the association between ACE-I/ARB and outcomes of mortality, cirrhosis decompensation, and hepatocellular carcinoma (HCC). In exploratory analysis, cause-specific competing risk models evaluated liver-related vs cardiovascular (CV)-related vs nonliver/non-CV-related mortality.

There were 904 ACE-I/ARB and 352 calcium channel blocker new initiators. In inverse probability treatment weighting Cox regression, ACE-I/ARB exposure was associated with reduced mortality (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.61-0.81, P < 0.001). In patients with compensated cirrhosis, ACE-I/ARB were not associated with hepatic decompensation or HCC. Cause-specific hazard models showed ACE-I/ARB exposure was associated with reduction in nonliver/non-CV-related mortality (cause-specific HR 0.49, 95% CI 0.38-0.62, P < 0.001) but not liver-related or CV-related mortality. In Child-Turcotte-Pugh A patients, ACE-I/ARB were associated with decreased CV-related mortality (cause-specific HR 0.41, 95% CI 0.26-0.65, P < 0.001).

ACE-I/ARB exposure was associated with reduced mortality, potentially through CV and other (renal, malignancy-related) mechanisms. In patients with compensated disease, ACE-I/ARB were not associated with hepatic decompensation or HCC. Future research should identify subsets of patients who benefit from ACE-I/ARB exposure.

Wilson disease (WD) is a potentially fatal metabolic disorder caused by the inactivation of the copper (Cu) transporter ATP7B, resulting in systemic Cu overload and fibroinflammatory liver disease. The molecular mechanism and effects of elevated Cu on cytoskeletal dynamics in liver fibrogenesis are not clear. Here, we tested the regulation of hepatic cytoskeleton and fibrogenesis with respect to Cu overload in WD. Atp7b-/- (knockout) mice with established liver disease, hepatocyte-specific Atp7b△Hep knockout mice without fibroinflammatory disease, and the age-and sex-matched controls were compared using Western blotting, real-time quantitative reverse transcription PCR (qRT-PCR), immunohistochemical (IHC) staining and transcriptomics (RNA-sequencing) analysis. In Atp7b-/- mice with developed liver disease, there is a significant increase in cytoskeletal protein expression with a reduction in α-tubulin acetylation. In these mice before the onset of liver pathology, no significant changes in cytoskeletal nor hepatic stellate cell activation are observed. As hepatic copper levels rise, an increase in cytoskeletal proteins with a decrease in acetylated-α-tubulin/α-tubulin ratio occurs. RNA-sequencing, qRT-PCR, and immunostaining confirm that the tubulin is upregulated at the transcriptional level and hepatocytes are the primary source of early tubulin increases before fibrosis. An increase in α-tubulin with a decrease in α-tubulin acetylation via Hdac6 and Sirt2 induction facilitates fibrosis as reflected by concomitant increases in desmin and α-SMA immunostaining in Atp7b-/- mice at 20 weeks. Moreover, strongly positive correlations between α-tubulin and α-tubulin deacetylase with the expression of liver fibrosis markers are observed in animal and human WD. Hepatocyte-specific Atp7b△Hep mice lack significant changes in tubulin as well as fibrosis despite hepatic steatosis. This study provides evidence that microtubule destabilization causes cytoskeletal rearrangement and facilitates hepatic stellate cell (HSC) activation and fibrosis in the murine model of WD. KEY MESSAGES: Hepatic cytoskeleton system is induced in Wilson disease. Hepatic microtubules acetylation is dysregulated in murine Wilson disease. Microtubules destabilization is positively associated with liver fibrosis in Wilson disease. Microtubules destabilization concomitant with fibrogenesis exacerbates WD progression.

Hepatocellular Carcinoma (HCC), a highly prevalent malignancy, poses a significant global health challenge. Its pathogenesis is intricate and multifactorial, involving a complex interplay of environmental and genetic factors. Viral hepatitis, excessive alcohol consumption, and cirrhosis are known to significantly elevate the risk of developing HCC. The underlying biological processes driving HCC are equally complex, encompassing aberrant activation of molecular signaling pathways, dysregulation of hepatocellular differentiation and angiogenesis, and immune dysfunction. This review delves into the multifaceted nature of HCC, exploring its etiology and the intricate molecular signaling pathways involved in its development. We examine the role of immune dysregulation in HCC progression and discuss the potential of emerging therapeutic strategies, including immune-targeted therapy and tumor-associated macrophage interventions. Additionally, we explore the potential of traditional Chinese medicine (TCM) monomers in inhibiting tumor growth. By elucidating the complex interplay of factors contributing to HCC, this review aims to provide a comprehensive understanding of the disease and highlight promising avenues for future research and therapeutic development.

Hepatitis B virus (HBV) infection is a significant contributor to the development of hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide. Iron, a central co-factor in various metabolic pathways, plays an essential role in liver function, but its dysregulation can lead to severe health consequences. Accumulation of iron within hepatic cells over time is linked to increased liver injury and is strongly associated with sensitive exposure to a range of conditions, including cirrhosis, fibrosis and ultimately, HCC. This review explores the intricate interplay between iron metabolism and HCC within the context of HBV infection. Hepatic iron overload can arise from liver injury and disruptions in iron homeostasis, causing hepatic necrosis, inflammation, and fibrosis, ultimately culminating in carcinogenesis. Moreover, alterations in serum iron components in HBV-related scenarios have been observed to impact the persistence of HBV infection. Notably, the progression of HBV-associated liver damage exhibits distinct characteristics at various stages of liver disease. In addition to elucidating the complex relationship between iron metabolism and HCC in the context of HBV infection, this review also investigates the prognostic implications of systemic iron levels for HCC. Furthermore, it aims to provide a comprehensive understanding of the intricate interplay between iron metabolism and HCC, extending the discussion to the context of hepatitis C virus (HCV) infection. By shedding light on these multifaceted connections, this review aims to contribute to our understanding of the pathogenesis of HBV-associated HCC and potentially identify novel therapeutic avenues for intervention.

Tenofovir alafenamide (TAF) is widely used for chronic hepatitis B (CHB) treatment due to its improved renal and bone safety compared to tenofovir disoproxil fumarate (TDF). However, emerging evidence suggests that TAF may adversely affect lipid metabolism, raising concerns about potential cardiovascular risks. A systematic review and meta-analysis following PRISMA guidelines was conducted. Studies comparing lipid profile changes in CHB patients receiving TAF, TDF, or entecavir (ETV) were retrieved from PubMed, Cochrane, and Embase. Primary outcomes included changes in total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Sensitivity analyses were performed to assess potential confounders, including lipid-lowering therapy. Trial sequential analysis (TSA) was used to evaluate the sufficiency of evidence. A total of 23 studies (5 RCTs, 18 observational) were included. Observational data showed significant increases in TC (MD = 10.74 mg/dL), TG (MD = 11.56 mg/dL), LDL (MD = 3.08 mg/dL), and HDL (MD = 7.51 mg/dL) with TAF versus TDF. Meta-analysis of RCTs confirmed these findings, showing TC (MD = 18.28 mg/dL), LDL (MD = 13.09 mg/dL), and HDL (MD = 4.95 mg/dL) elevations. TAF is associated with increased lipid levels, likely due to the loss of TDF's lipid-lowering effect. While its cardiovascular risk remains uncertain, clinicians should monitor lipid profiles in CHB patients on TAF, particularly those at high cardiovascular risk.

The food safety risks posed by exposure to polystyrene microplastics (PS-MPs) and bisphenol A (BPA) have become an issue worldwide. However, the toxic effects of PS-MPs and BPA coexposure on the mammalian liver remain elusive. In this study, we found that PS-MPs and BPA coexposure have synergistic toxic effects on AML12 cells and the mouse liver. Histopathological staining revealed excessive accumulation of the extracellular matrix in the coexposure liver. Co-exposure to PS-MPs and BPA downregulated Bmal1 and E-cad both in vitro and in vivo. Additionally, Bmal1-/- AML12 cells and liver-specific Bmal1-/- mice exhibited significantly reduced E-cad levels, with no significant reduction under PS-MPs and BPA coexposure. Notably, overexpression of BMAL1 and CLOCK significantly enhanced luciferase activity driven by the E-cad gene intron region (containing an E-box cis-element). These results demonstrated that coexposure to PS-MPs and BPA contributed to the development of liver fibrosis by inhibiting the BMAL1/E-cad signaling pathway.

Complex diseases often undergo abrupt transitions from pre-disease to disease states, with the pre-disease state is typically unstable but potentially reversible through timely intervention. Detecting these critical transitions is crucial. We propose a model-free method, Local Network Wasserstein Distance (LNWD), for identifying critical transitions/pre-disease states in complex diseases using single sample analysis. LNWD measures statistical perturbations in normal samples caused by diseased samples using the Wasserstein distance, and identifies critical states by observing LNWD score changes. Applied to KIRP, KIRC, LUAD, ESCA (TCGA datasets) and GSE2565, GSE13268 (GEO datasets), the method successfully identified critical states in six disease datasets. This single-sample, local network-based approach provides early warning signals for medical diagnosis and holds great potential for personalized disease diagnosis.

Several liver diseases have been associated with the Tudor staphylococcal nuclease (Tudor-SN) protein. Our previous results demonstrated that, in comparison to wild-type (WT) mice, systemic overexpression of Tudor-SN in transgenic (Tg) mice (Tudor-SN-Tg) ameliorates obesity-induced insulin resistance and hepatic steatosis. In this study, we observed an inverse correlation in the expression levels of Tudor-SN and profibrogenic factors, such as alpha-smooth muscle actin (α-SMA) and collagen alpha-1(I) chain (COL1A1), in liver tissue samples between Tudor-SN-Tg and WT mice. The correlation was further validated in hepatic fibrotic tissues from patients with cirrhosis and fibrosis. Utilizing a carbon tetrachloride (CCl4)-induced hepatic fibrosis model, we observed that Tudor-SN attenuated hepatic fibrosis in mice. Tudor-SN was abundantly expressed in hepatic stellate cells (HSCs). In the Tudor-SN-Tg group, primary HSCs showed stellate-like morphology as well as reduced in vitro proliferation and chemotactic ability compared to the WT group. Pseudotime series analysis of HSCs further showed the role of Tudor-SN during the dynamic evolution of HSC activation. Reduced Tudor-SN expression facilitated the in vitro activation of LX-2 cells. Furthermore, primary HSC cells from WT and Tudor-SN knockout (KO) mice were isolated for RNA-sequencing analysis. The findings suggested that Tudor-SN may regulate the activation of primary HSCs by influencing lipid metabolism, translation initiation, immune response, and the extracellular matrix. In summary, we identified Tudor-SN as a newly identified regulator involved in the transition of quiescent HSCs to activated states, shedding light on the antifibrotic impact of Tudor-SN expression in the development of hepatic fibrosis.

BackgroundThe prevalence of hepatosteatosis, or fatty liver disease, has been increasing globally in recent years largely due to increasing rates of obesity, diabetes, and metabolic syndrome.PurposeTo examine the platelet to lymphocyte ratio (PLR) reflection on the hepatosteatosis stage.Material and MethodsWe evaluated healthy individuals who applied to the check-up department in our hospital. The platelet and lymphocyte counts from blood tests, along with upper abdominal ultrasound results obtained as part of routine diagnostic check-ups, results recorded retrospectively, between November 2022 and April 2024.ResultsA total 748 participants were included in the study. All participants were divided in three groups according to hepatosteatosis stages.The PLR levels were highest in the stage 1 hepatosteatosis group. There was statistical significance in PLR levels between stage 1 and 3 hepatosteatosis (P = 0003). In addition, PLR levels were higher in stage 2 than in stage 3, which was also statistically significant (P = 0037).ConclusionThese results could help in early detection and monitoring of disease progression in patients with hepatoteatosis. Lower PLR values (<115.26) in advanced stages might prompt closer monitoring or more aggressive interventions to prevent progression to fibrosis.

Chronic liver injury characterized by unresolved hepatitis leads to fibrosis, potentially progressing to cirrhosis and hepatocellular carcinoma. Effective treatments for halting or reversing liver fibrosis are currently lacking. This study investigates the potential of HDAC6 as a therapeutic target in liver fibrosis. We synthesized two selective HDAC6 inhibitors, DR-3 and FDR2, and assessed their effects on hepatic stellate cell (HSC) activation and liver fibrosis using human precision cut liver slices (hPCLS). Molecular docking, deacetylation inhibition assays, and various cellular assays were employed to evaluate the specificity and anti-fibrotic efficacy of these inhibitors. DR-3 and FDR2 demonstrated high selectivity for HDAC6 over HDAC1, significantly inhibiting HSC activation markers and fibrogenic gene expression. Both inhibitors increased acetylation of α-tubulin and suppressed TGF-β1-induced SMAD signaling in HSCs. In human precision cut liver slices (hPCLS), DR-3 and FDR2 reduced fibrogenic protein levels and collagen deposition. The selective inhibition of HDAC6 by DR-3 and FDR2 effectively reduces HSC activation and fibrogenesis in liver models, supporting further investigation of HDAC6 inhibitors as potential anti-fibrotic therapies.

Radiation-induced disease (RID) is the most important factor limiting the radiotherapy dose for malignant tumors, especially for patients with organ insufficiency or chronic inflammation. In this paper, it studied the changes in the microenvironment after radiation exposure from the perspectives of molecular biology, cell biology and histopathology, and first proposed a novel model of the radiation microenvironment to depict radiation-induced spatial heterogeneity. The radiation microenvironment was divided into the VIM model: vascular microenvironment, inflammatory microenvironment, and metabolic microenvironment according to the special cell functions, molecular expressions and pathological structures after radiation. The structural functions of each microenvironment were explored to provide the new theoretical basis for molecular target prediction, radiation damage assessment, prevention and treatment of radiation-induced disease, and using radiation-induced liver injury as a template to depict the VIM model.

Aim: The liver is the major source of circulating insulin-like growth factor (IGF)-I. Serum IGF-I levels are decreased in cirrhotic patients depending on severity. IGF-I administration was shown to improve liver function in patients and animal models of liver cirrhosis. However, controversy exists as to whether IGF-I stimulates or reduces fibrosis in the liver. The effects of IGF-I on collagen accumulation by hepatic stellate cells (HSCs) and its mechanisms were studied. Methods: A moderately activated HSC clone was used to determine the effect of IGF-I administration on the collagen production system, including its degradation. The intracellular signaling system was also studied in the cells stimulated by IGF-I. Results: IGF-I treatment reduced total amounts of collagen deposition in a dose-related manner, while DNA synthesis was stimulated by IGF-I. IGF-I treatment did not affect transforming growth factor-beta levels and type I procollagen mRNA expression. Expression of matrix metalloproteinase (MMP)-2 and -9 was upregulated, and tissue inhibitor of metalloproteinase (TIMP)-1 expression was downregulated by IGF-I treatment. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), suppressed phosphorylation of 70 kDa ribosomal protein S6 kinase and eukaryotic initiation factor 4E-binding protein 1, and abrogated IGF-I-induced increase in MMP-2 and -9 expression and decrease in TIMP-1 expression. Conclusions: IGF-I has the ability to stimulate the collagen degradation system by HSCs through an mTOR-dependent pathway independent of modulation of the activation state of HSCs.

Carbon tetrachloride (CCl4) is a well-known hepatotoxin. This work aimed to assess the therapeutic anti-inflammatory immune potentials of the seaweeds Padina pavonia and Jania rubens extracts on carbon tetrachloride (CCL4)-caused liver damage in mice. Our experimentation included two testing regimens: pre-treatment and post-treatment of P. pavonia and J. rubens extracts in CCL4/mice. Pre-treatment and post-treatment of P. pavonia and J. rubens extracts in CCL4/mice increased WBCs count and lymphocytes relative numbers and reduced the neutrophils and monocytes relative numbers. Pre-treatment and post-treatment of CCL4/mice with P. pavonia and J. rubens extracts significantly reduced the release amounts of pro-inflammatory cytokines TNF-α and IL-6 and significantly inhibited the increased CRP level. Furthermore, pre-treatment and post-treatment of CCL4/mice with P. pavonia and J. rubens extracts recovered the activities of GSH, and significantly decreased MDA level. CCL4/mice pre-treated and post-treated with P. pavonia and J. rubens extracts decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Pre- and post-treatment of CCL4/mice with the P. pavonia and J. rubens extracts ameliorated the liver damages caused by CCl4 and significantly inhibited the necrotic area, indicating hepatic cell death and decreased periportal hepatic degeneration, fibrosis, and inflammation.

Cigarette smoke (CS), an intricate blend comprising over 4000 compounds, induces abnormal cellular reactions that harm multiple tissues. Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease (CLD), encompassing non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Recently, the term NAFLD has been changed to metabolic dysfunction-associated steatotic liver disease (MASLD), and NASH has been renamed metabolic dysfunction-associated steatohepatitis (MASH). A multitude of experiments have confirmed the association between CS and the incidence and progression of MASLD. However, the specific signaling pathways involved need to be updated with new scientific discoveries. CS exposure can disrupt lipid metabolism, induce inflammation and apoptosis, and stimulate liver fibrosis through multiple signaling pathways that promote the progression of MASLD. Currently, there is no officially approved efficacious pharmaceutical intervention in clinical practice. Therefore, lifestyle modifications have emerged as the primary therapeutic approach for managing MASLD. Smoking cessation and the application of a series of natural ingredients have been shown to ameliorate pathological changes in the liver induced by CS, potentially serving as an effective approach to decelerating MASLD development. This article aims to elucidate the specific signaling pathways through which smoking promotes MASLD, while summarizing the reversal factors identified in recent studies, thereby offering novel insights for future research on and the treatment of MASLD.

Background: Portal hypertension is a major complication of chronic liver diseases, leading to serious issues such as esophageal variceal bleeding. The increase in portal vein pressure is driven by both an organic component and a functional component, including tonic contraction of hepatic stellate cells. These processes result in a pathological rise in intrahepatic vascular resistance, stemming from partial impairment of hepatic microcirculation, which is further exacerbated by abnormalities in extrahepatic vessels, including increased portal blood flow. Objectives: This review aims to provide a comprehensive overview of the evolving pharmacological therapies for portal hypertension, with consideration and discussion of pathophysiological mechanisms, clinical complications, and pharmacogenetic considerations, highlighting potential directions for future research. Methods: A review of recent literature was performed to evaluate current knowledge and potential therapeutic strategies in portal hypertension. Results: For over 35 years, non-selective beta-blockers have been the cornerstone therapy for portal hypertension by reducing portal vein inflow as an extrahepatic target, effectively preventing decompensation and variceal hemorrhages. However, since not all patients exhibit an adequate response to non-selective beta-blockers (NSBBs), and some may not tolerate NSBBs, alternative or adjunctive therapies that enhance the effects of NSBBs on portal pressure are being investigated in preclinical and early clinical studies. Conclusions: A better understanding of pharmacogenetic factors and pathophysiological mechanisms could lead to more individualized and effective treatments for portal hypertension. These insights highlight potential directions for future research.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder closely linked to metabolic syndrome. Identifying novel, easily measurable biomarkers could significantly enhance the diagnosis and management of NAFLD in clinical settings. Recent studies suggest that immunoinflammatory biomarkers-specifically, the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR)-may offer diagnostic value for NAFLD. However, the effectiveness of these biomarkers has not been comprehensively assessed in this patient population. This systematic review and meta-analysis aimed to evaluate the association between these immunoinflammatory biomarkers and NAFLD. As of August 8, 2024, databases including PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus were systematically searched to compare NLR, PLR, and LMR levels in NAFLD patients and healthy controls. Study quality was assessed using the Newcastle-Ottawa Scale, and standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated (PROSPERO registry number: CRD42024580812). A total of 20 studies were included in the meta-analysis. Results indicated that NAFLD patients had significantly higher NLR levels (SMD = 0.43; 95% CI 0.28-0.58; p < 0.001) and lower PLR levels (SMD = - 0.29; 95% CI - 0.41 to - 0.17; p < 0.001) compared to controls. However, no significant difference in LMR was observed between NAFLD patients and controls(SMD = 0.08; 95% CI - 0.00 to 0.17; p = 0.051). These findings suggest that NLR and PLR may hold promise as diagnostic markers for NAFLD, while LMR appears to have limited diagnostic utility. Further research is warranted to explore the potential role of these biomarkers in tracking disease progression.

Nonalcoholic fatty liver disease (NAFLD) is the extremely usual reason of chronic liver disease, extending from simple hepatic steatosis (HS), nonalcoholic steatohepatitis (NASH) to advanced hepatic fibrosis and cirrhosis. Though orlistat is a Food and Drug Administration (FDA) approved drug for long-duration management of obesity, few cases of severe hepatic insult were declared. Melatonin is an efficient antioxidant; it also regulates metabolic processes that lead to fat accumulation and obesity.

The current research aimed to compare the impact of orlistat, melatonin, and their combination on the structural changes of the hepatic tissue of adult male albino rats supplied with high fat diet (HFD).

Thirty adult male albino rats divided into five groups. Liver specimens were divided into two parts. One-half was processed to obtain paraffin blocks, and the other half was processed to obtain semithin sections. Morphometric study and statistical analysis were done.

Hepatic tissue from the HFD group showed steatosis, ballooning, and inflammation and all these parameters were moderately improved - except for inflammation which worsened with therapy. Combined orlistat and melatonin-treated groups showed marked improvement of all parameters as well as marked improvement in the hepatic fibrosis.Orlistat/Melatonin combination therapy is both safe and effective in comparison to orlistat and melatonin monotherapy.

Liver disease, responsible for two million annual deaths, causes Chronic Liver Disease (CLD) and cirrhosis, causing roughly a million deaths yearly. Treatment options for liver injury induced by hepatotoxicity vary, including medication (N-acetylcysteine, corticosteroids, and ursodeoxycholic acid), lifestyle changes, and sometimes liver transplant. However, effectiveness varies, and some treatments carry risks and side effects, highlighting the need for improved therapeutic approaches. Murraya koenigii (MK) is known for its hepatoprotective, antioxidant, anti-inflammatory, anti-microbial, nephroprotective, hepatoprotective, gastroprotective, cardioprotective, neuroprotective, wound-healing, anti-cancerous and immunomodulatory effects, etc. This review highlights the effectiveness of MK against liver damage induced by heavy metals, drug abuse, xenobiotics, etc. A comprehensive search across multiple databases like PubMed, Google Scholar, and others for articles on various hepatotoxicants and hepatoprotective activity of MK was conducted. The researchers applied specific search terms and limits, resulting in 149 eligible articles for final analysis, meeting predetermined inclusion criteria and excluding irrelevant studies. According to the available literature, the phytochemical components of MK, such as flavonoids, tannins, and alkaloids present in various extracts, play a crucial role in reversing the hepatotoxic effects by modifying oxidative and ER stresses, re-establishing the hepatic biochemical markers and enzymes involved in metabolism denoting ameliorative activity, and controlling the expression of pro-inflammatory cytokines. To conclude, this review highlights that MK has great potential as a natural hepatoprotective agent, providing a versatile defense against a range of injuries caused by heavy metals, xenobiotics, and common hepatotoxic agents.

This review explores various biliary tract diseases caused by different organisms, including cholelithiasis, hepatolithiasis, and choledocholithiasis. The biliary tract's primary functions include collecting, storing, concentrating, and delivering bile juice produced by the liver. Neurohormonal systems involving the vagus and splanchnic nerves, alongside cholecystokinin, regulate gallbladder movement during fasting and digestion. Under normal conditions, bile acids play a crucial role, with approximately 95% being reabsorbed by the intestinal epithelium and returned to the liver via the portal vein system. The liver, often hailed as a miracle worker, detoxifies, purifies, and regenerates, performi ng essential functions in the body. Recent research indicates that the gallbladder, akin to the intestine, harbors a diverse microbiota. Additionally, the biliary mucosa features chemical, mechanical, and immunological barriers that promote immunological tolerance. Hepatotoxicity remains a significant global health concern and a leading cause of mortality. Providing clear and accurate information on liver toxicity is critical, especially in the context of medication safety and public health. By refining these elements, this review can effectively convey the complexity and importance of biliary tract diseases and liver function in health and disease contexts.

Progression of chronic liver injury to fibrosis, abnormal liver regeneration, and HCC is driven by a dysregulated dialog between epithelial cells and their microenvironment, in particular immune, fibroblasts, and endothelial cells. There is currently no antifibrogenic therapy, and drug treatment of HCC is limited to tyrosine kinase inhibitors and immunotherapy targeting the tumor microenvironment. Metabolic reprogramming of epithelial and nonparenchymal cells is critical at each stage of disease progression, suggesting that targeting specific metabolic pathways could constitute an interesting therapeutic approach. In this review, we discuss how modulating intrinsic metabolism of key effector liver cells might disrupt the pathogenic sequence from chronic liver injury to fibrosis/cirrhosis, regeneration, and HCC.

Hepatocellular carcinoma (HCC) mainly depends on liver fibrosis/cirrhosis, which is regulated by tumor cells and the tumor microenvironment (TME), and is a crucial factor in tumor progression. This study aimed to identify abnormally expressed miR-500a-3p in the hepatitis-cirrhosis-HCC pathway and explored the roles of miR-500a-3p in HCC progression. A clinical cohort of patients with HCC is studied retrospectively. Subsequently, the role of miR-500a-3p transported by HCC exosomes in hepatic stellate cell (HSC) activation, hepatoma growth and invasion, and immune cell differentiation is determined by in vitro and in vivo experiments. In clinical tissues, miR-500a-3p is significantly enriched in HCC and cirrhosis tissues, and co-expression of the immune marker CD4 or PD-L1 significantly correlates with low survival rates in patients. Extracellular miR-500a-3p is taken up by HSC and PBMC, which promotes the secretion of the cytokines TGF-β1 and IL-10, increases PD-L1 expression in HSC, and stabilizes PD-1 expression in PBMC to affect the TME. Moreover, miR-500a-3p is associated with CD4+ T-cell exhaustion and Treg differentiation and is significantly associated with increased tumorigenicity in in situ mouse HCC models. Mechanistically, HCC-derived exosomal miR-500a-3p directly influences SOCS2 to regulate the JAK3/STAT5A/STAT5B signaling pathway. MiR-500a-3p promotes the growth and migration of HCC through the SOCS2/JAK3/STAT5A/STAT5B axis.

Repetitive hepatic damage resulting from viral hepatitis, toxins, and alcohol abuse induces chronic inflammation and excessive accumulation of the extracellular matrix, leading to the development of liver cirrhosis. Substance P (SP) promotes endogenous wound healing by mobilizing bone marrow stem cells and stimulating anti-inflammatory responses. This study aimed to investigate whether SP exerts a therapeutic effect on liver fibrosis by recruiting endogenous stem cells and modulating immune responses. A non-clinical model of liver cirrhosis was established through repeated injections of thioacetamide and recombinant leptin. After confirming liver fibrosis, SP was administered intravenously for 6 weeks. SP treatment decreased the formation of hepatic micronodules on the external surface of the liver and the infiltration of immune cells. Furthermore, SP treatment notably reduced the deposition of collagen and the activation of hepatic stellate cells, concomitant with decreased levels of transforming growth factor-β1 and matrix metalloproteinase activity. In the context of severe hepatic damage, SP increased the number of circulating stem cells, leading to the restoration of the reparative stem cell pool in the bone marrow. The findings of this study suggest that SP alleviates liver fibrosis by modulating the mobilization of functional stem cells and the immune response.

To study the potential of viscoelastic parameters such as liver stiffness, loss tangent (marker of viscous properties) and viscoelastic dispersion to detect hepatic inflammation by in-vivo and ex-vivo MR elastography (MRE) at low and high vibration frequencies.

15 patients scheduled for liver tumor resection surgery were prospectively enrolled in this IRB-approved study and underwent multifrequency in-vivo MRE (30-60Hz) at 1.5-T prior to surgery. Immediately after liver resection, tumor-free tissue specimens were examined with ex-vivo MRE (0.8-2.8 kHz) at 0.5-T and histopathologic analysis including NAFLD activity score (NAS) and inflammation score (I-score) as sum of histological sub-features of inflammation.

In-vivo, in regions where tissue samples were obtained, the loss tangent correlated with the I-score (R = 0.728; p = 0.002) and c-dispersion (stiffness dispersion over frequency) correlated with lobular inflammation (R = -0.559; p = 0.030). In a subgroup of patients without prior chemotherapy, c-dispersion correlated with I-score also in the whole liver (R = -0.682; p = 0.043). ROC analysis of the loss tangent for predicting the I-score showed a high AUC for I ≥ 1 (0.944; p = 0.021), I ≥ 2 (0.804; p = 0.049) and I ≥ 3 (0.944; p = 0.021). Ex-vivo MRE was not sensitive to inflammation, whereas strong correlations were observed between fibrosis and stiffness (R = 0.589; p = 0.021), penetration rate (R = 0.589; p = 0.021), loss tangent (R = -0.629; p = 0.012), and viscoelastic model parameters (spring-pot powerlaw exponent, R = -0.528; p = 0.043; spring-pot shear modulus, R = 0.589; p = 0.021).

Our results suggest that c-dispersion of the liver is sensitive to inflammation when measured in-vivo in the low dynamic range (30-60Hz), while at higher frequencies (0.8-2.8 kHz) viscoelastic parameters are dominated by fibrosis.

Cirrhosis, which represents the end stage of liver fibrosis, remains a life-threatening condition without effective treatment. Therefore, prevention of the progression of liver fibrosis through lifestyle habits such as diet and exercise is crucial. The functional food AHCC, a standardized extract of cultured Lentinula edodes mycelia produced by Amino Up Co., Ltd. (Sapporo, Japan)] has been reported to be effective in improving the pathophysiology of various liver diseases. In this study, the aim was to analyze the influence of AHCC on hepatic stellate cells, which are responsible for liver fibrosis. Eight-week-old male C57BL6/j mice were induced with liver fibrosis by intraperitoneal injection of carbon tetrachloride. Simultaneously, they were orally administered 3% AHCC to investigate its impact on the progression of liver fibrosis. Using the human hepatic stellate cell (HHSteC) line, we analyzed the influence of AHCC on the expression of molecules related to hepatic stellate cell activation. The administration of AHCC resulted in reduced expression of collagen1a, α smooth muscle actin (αSMA), and heat shock protein 47 in the liver. Furthermore, the expression of cytoglobin, a marker for quiescent hepatic stellate cells, was enhanced. In vitro study, it was confirmed that AHCC inhibited αSMA by inducing cytoglobin via upregulating the stress-activated protein kinase/Jun NH2-terminal kinase (SAPK/JNK) pathway through Toll-like receptor (TLR) 2. In addition, AHCC suppressed collagen1a production by hepatic stellate cells through TLR4-NF-κβ pathway. AHCC was suggested to suppress hepatic fibrosis by inhibition of hepatic stellate cells activation. Daily intake of AHCC from mild fibrotic stages may have the potential to prevent the progression of liver fibrosis.NEW & NOTEWORTHY AHCC, a standardized extract of cultured Lentinula edodes mycelia, suppresses liver fibrosis progression by induction of cytoglobin via the Toll-like receptor 2 (TLR2)-stress-activated protein kinase/Jun NH2-terminal kinase (SAPK/JNK) pathway and the inhibition of collagen production via the TLR4-NFκβ pathway in hepatic stellate cells. Daily oral administration of AHCC from the stage of MASLD may have the potential to prevent disease progression to MASH with fibrosis.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has reached an epidemic rise worldwide. The disease is a constellation of a broad range of metabolic and histopathologic abnormalities. It begins with hepatic steatosis and progresses to metabolic dysfunction-associated steatohepatitis (MASH), including hepatic fibrosis, apoptosis, and cell injury. Despite ample research effort, the pathogenesis of the disease has not been fully delineated. Whereas insulin resistance is implicated in the early stages of the disease, its role in hepatic fibrosis remains controversial. We have focused our studies on the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in hepatocytes and endothelial cells in the metabolic and histopathological dysregulation in MASH. Patients with MASH exhibit lower hepatic CEACAM1 with a progressive decline in hepatocytes and endothelial cells as the fibrosis stage advances. In mice, conditional deletion of CEACAM1 in hepatocytes impairs insulin clearance to cause hyperinsulinemia-driven insulin resistance with steatohepatitis and hepatic fibrosis even when mice are fed a regular chow diet. In contrast, its conditional deletion in endothelial cells causes inflammation-driven hepatic fibrosis without adversely affecting metabolism (mice remain insulin-sensitive and do not develop hepatic steatosis). Thus, this review provides in vivo evidence that supports or discards the role of insulin resistance in liver injury and hepatic fibrosis.

The lack of effective non-invasive diagnostic methods for liver fibrosis hinders timely treatment for chronic hepatitis B (CHB) patients, leading to the progression of advanced liver disease. Circulating microRNAs offer a non-invasive approach to fibrosis assessment. MicroRNA-15a/16-1 (miR-15a/16) was reported to be implicated in fibrosis development, but the role of plasma miR-15a/16 in liver fibrosis assessment remains poorly understood. This study explored the importance of plasma miR-15a/16 in assessing liver fibrosis severity of CHB patients.

Quantitative PCR was utilized to measure the levels of plasma miR-15a/16 in 435 patients with CHB and 74 healthy controls. We assessed the correlation between plasma miR-15a/16 levels and liver fibrosis and cirrhosis using Pearson correlation coefficients, multivariate linear and logistic regression models, and smooth curve fitting. Utilizing the receiver operating characteristic (ROC) curve, we examined the diagnostic potential of plasma miR-15a/16 in severe fibrosis and cirrhosis.

Plasma levels of miR-15a/16 in patients with CHB were significantly reduced compared to those in healthy controls. In the CHB cohort, levels were notably decreased in individuals with severe fibrosis or cirrhosis compared to those without severe fibrosis or cirrhosis. Plasma miR-15a/16 levels exhibited a negative relationship with the severity of liver fibrosis, gradually decreasing as the histological fibrosis stage progressed from S0 to S4. Reduced levels of plasma miR-15a/16 were linked to an elevated risk of severe liver fibrosis (miR-15a: odds ratio [OR] = 0.243; 95 % confidence interval [CI]: 0.138, 0.427; miR-16: OR = 0.201; 95 % CI: 0.097, 0.417) and cirrhosis (miR-15a: OR = 0.153; 95 % CI: 0.079, 0.298; miR-16: OR = 0.064; 95 % CI: 0.025, 0.162). MiR-15a achieved an area under the ROC curve of 0.886 and 0.832 for detecting moderate-to-severe fibrosis (S2-S4) and cirrhosis, respectively. MiR-16 demonstrated similar diagnostic values.

Plasma miR-15a/16 levels were negatively correlated with the severity of liver fibrosis in CHB patients and could serve as a new non-invasive indicator in evaluating liver fibrosis.

This study aimed to explore the key genes involved in the pathophysiological process of liver fibrosis and develop a novel predictive model for noninvasive assessment of significant liver fibrosis patients.

Differentially expressed genes (DEGs) were identified using the Limma package. The hub genes were explored using the CytoHubba plugin app and validated in GEO datasets and cell models. Furthermore, serum LTBP2 was measured in liver fibrosis (LF) patients with biopsy-proven by ELISA. All patients' clinical characteristics and laboratory results were analyzed. Finally, multivariate logistic regression analysis was used to construct the model for visualization by nomogram. Area under the receiver operating characteristic curve (AUROC) analysis, calibration curves, and decision curve analysis (DCA) certify the accuracy of the nomogram.

RNA sequencing was performed on the liver tissues of 66 biopsy-proven HBV-LF patients. After multiple analyses and in vitro simulation of HSC activation, LTBP2 was found to be the most associated with HSC activation regardless of the causes. Serum LTBP2 expression was measured in 151 patients with biopsy, and LTBP2 was found to increase in parallel with the fibrosis stage. Multivariate logistic regression analysis showed that LTBP2, PLT and AST levels were demonstrated as the independent prediction factors. A nomogram that included the three factors was tabled to evaluate the probability of significant fibrosis occurrence. The AUROC of the nomogram model was 0.8690 in significant fibrosis diagnosis.

LTBP2 may be a new biomarker for liver fibrosis patients. The nomogram showed better diagnostic performance in patients.

Liver fibrosis is a common pathway shared by all forms of progressive chronic liver disease. There is an unmet clinical need for noninvasive imaging tools to diagnose and stage fibrosis, which presently relies heavily on percutaneous liver biopsy. Here we explored the feasibility of using a novel type I collagen-targeted manganese (Mn)-based MRI probe, Mn-CBP20, for liver fibrosis imaging. In vitro characterization of Mn-CBP20 demonstrated its high binding affinity for human collagen (K d = 9.6 μM), high T1-relaxivity (48.9 mM-1s-1 at 1.4T and 27°C), and kinetic inertness to Mn release under forcing conditions. We demonstrated MRI using Mn-CBP20 performs comparably to previously reported gadolinium-based type I collagen-targeted probe EP-3533 in a mouse model of carbon tetrachloride-induced liver fibrosis, and further demonstrate efficacy to detect fibrosis in a diet-induced mouse model of metabolically-associated steatohepatitis. Biodistribution studies using the Mn-CBP20 radio-labeled with the positron-emitting 52Mn isotope demonstrate efficient clearance of Mn-CBP20 primarily via renal excretion. Mn-CBP20 represents a promising candidate that merits further evaluation and development for molecular imaging of liver fibrosis.

Transforming growth factor (TGF)β1 induces plasma membrane (PM) accumulation of glucose transporter 1 (Glut1) required for glycolysis of hepatic stellate cells (HSCs) and HSC activation. This study aimed to understand how Glut1 is anchored/docked onto the PM of HSCs.

HSC expression of protein kinase M zeta isoform (PKMζ) was detected by reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescence. PKMζ level was manipulated by short hairpin RNA (shRNA) or overexpression; HSC activation was assessed by cell expression of activation markers; PM Glut1, glucose uptake, and glycolysis of HSCs were analyzed by biotinylation, 2-NBDG-based assay, and Seahorse Glycolysis Stress Test. Phospho-mutants of vasodilator-stimulated phosphorylated protein (VASP) were created by site-directed mutagenesis. TGFβ transcriptome was obtained by RNA sequencing. Single-cell RNA sequencing datasets and immunofluorescence were leveraged to analyze PKMζ expression in cancer-associated fibroblasts (CAFs) of colorectal liver metastases. Function of HSC PKMζ was determined by tumor/HSC co-implantation study.

Primary human and murine HSCs express PKMζ, but not full-length PKCζ. PKMζ knockdown suppresses, whereas PKMζ overexpression potentiates PM accumulation of Glut1, glycolysis, and HSC activation induced by TGFβ1. Mechanistically, PKMζ binds to and induces VASP phosphorylation at serines 157 and 239 facilitating anchoring/docking of Glut1 onto the PM of HSCs. PKMζ expression is increased in the CAFs of murine and patient colorectal liver metastases compared with quiescent HSCs. Targeting PKMζ suppresses transcriptome, CAF activation of HSCs, and colorectal tumor growth in mice.

Because HSCs are also a major contributor of liver fibrosis, our data highlight PKMζ and VASP as targets to inhibit metabolic reprogramming, HSC activation, liver fibrosis, and the pro-metastatic microenvironment of the liver.

Zinc plays a pivotal role in tissue regeneration and maintenance being as a central cofactor in a plethora of enzymatic activities. Hypozincemia is commonly seen with chronic liver disease and is associated with an increased risk of liver fibrosis development and hepatocellular carcinoma. Previously favorable effects of zinc supplementation on liver fibrosis have been shown. However, the underlying mechanism of this effect is not elucidated. Liver fibrosis was induced in mice by using CCl4 injection, followed by treatment with zinc chloride (ZnCl2) both at fibrotic and sham groups, and their hepatocytes were isolated. Our results showed that the administration of ZnCl2 restored the depleted cytosolic zinc levels in the hepatocytes isolated from the fibrotic group. Also, alpha-smooth muscle actin (αSMA) expression in hepatocytes was decreased, indicating a reversal of the fibrotic process. Notably, ZIP14 expression significantly increased in the fibrotic group following ZnCl2 treatment, whereas in the sham group ZIP14 expression decreased. Chromatin immunoprecipitation (ChIP) experiments revealed an increased binding percentage of Metal-regulatory transcription factor 1 (MTF1) on ZIP14 promoter in the hepatocytes isolated from fibrotic mice compared to the sham group after ZnCl2 administration. In the same group, the binding percentage of the histone deacetylase HDAC4 on ZIP14 promoter decreased. Our results suggest that the ZnCl2 treatment ameliorates liver fibrosis by elevating intracellular zinc levels through MTF1-mediated regulation of ZIP14 expression and the reduction of ZIP14 deacetylation via HDAC4. The restoration of intracellular zinc concentrations and the modulation of ZIP14 expression by zinc orchestrated through MTF1 and HDAC4, appear to be essential determinants of the therapeutic response in hepatic fibrosis. These findings pave the way for potential novel interventions targeting zinc-related pathways for the treatment of liver fibrosis and associated conditions.