Background and aims: Hepatic fibrosis lacks broadly effective therapy, partly because hepatocyte–derived signals governing hepatic stellate cell (HSC) activation remain incompletely defined. METTL3, the catalytic core subunit of the N6–methyladenosine (m6A) methyltransferase complex, has been proven to participate in the progression of liver fibrosis, yet its non–canonical functions in injured hepatocytes remain undefined. We investigated how hepatocyte METTL3 promotes paracrine HSC activation.Methods: Human fibrotic liver tissues and two mouse hepatic fibrosis models were analyzed in this study, including carbon tetrachloride (CCl4)–induced toxic liver fibrosis and 3,5–diethoxycarbonyl–1,4–dihydrocollidine (DDC)–induced cholestatic liver fibrosis. Germline heterozygous METTL3–deficient mice and METTL3–overexpressing THLE–2 cells were applied for loss– and gain–of–function experiments. The functional requirement for ARAF, m6A enrichment of ARAF mRNA, mitochondrial dynamics, reactive oxygen species, plasma–membrane integrity, lactate release and HSC activation were assessed using RNA interference, MeRIP–seq, omics analyses, imaging and Transwell co–culture.Results: METTL3 was increased in fibrotic human and mouse liver. Heterozygous METTL3 deficiency attenuated fibrosis in both models, whereas METTL3 overexpression enhanced profibrotic signaling and paracrine HSC activation. Mechanistically, METTL3 associated with ARAF and enhanced ARAF–ERK1/2 signaling through a mechanism not primarily explained by altered ARAF m6A enrichment. This response was accompanied by increased Drp1S616 phosphorylation, mitochondrial fission and mitochondrial superoxide–associated fluorescence. Mitochondrial oxidative stress promoted NINJ1 upregulation and NINJ1–dependent plasma–membrane integrity loss, accompanied by LDH and lactate release. Hepatocyte–derived lactate subsequently promoted HSC activation together with TGF–β1/Smad3 signaling.Conclusions: Hepatocyte METTL3 promotes liver fibrosis through a METTL3–ARAF–ERK–Drp1–NINJ1 axis linking mitochondrial stress to NINJ1–dependent lactate release and paracrine HSC activation.​

Hypoxia, which represents a key pathological feature of gastric mucosal disorders, exacerbates mitochondrial oxidative stress through dysregulated cellular responses. However, the underlying mechanism of mitochondrial oxidative stress under hypoxia during gastric mucosal epithelial injury in portal hypertensive gastropathy (PHG) is not fully understood. To assess the impact of mitochondrial oxidative stress under hypoxic conditions during gastric mucosal epithelial injury in the PHG, mucosal tissues from patients with PHG and healthy individuals were collected. Furthermore, portal hypertension (PHT)-induced mouse PHG models and hypoxia-induced cell models were established. The roles of hypoxia-induced mitochondrial oxidative stress and glycolytic reprogramming in gastric mucosal epithelial injury were analysed. The findings demonstrated that mitochondrial oxidative stress is significantly elevated under hypoxic conditions, leading to an increase in reactive oxygen species (ROS) generation. This process contributes to gastric mucosal epithelial damage in both patients with PHG and mice with PHT. Notably, treatment with the ROS scavenger Mito-TEMPO reduced hypoxia-induced gastric mucosal injury in mice with PHT and mitigated cellular damage caused by hypoxia in a normal human gastric mucosal epithelial cell line (GES-1). Mitochondrial oxidative stress was shown to be associated with lactate dehydrogenase A upregulation, impaired ATP production and increased lactic acid release in gastric epithelial cells, all of which contribute to epithelial injury in the PHG. Therefore, hypoxia-induced mitochondrial oxidative stress has emerged as a promising therapeutic target for PHG.

To compare serological and CT imaging parameters between the mild and severe portal hypertensive gastropathy (PHG) group, and find out the non-invasive predictive markers for PHG severity based on these differences. Three hundred one patients were enrolled in our retrospective study. The PHG severity was assessed by esophagogastroduodenoscopy (EGD), and serological markers were measured within 48 h before EGD, and CT scans were performed within one week after EGD. Differences in age, gender, etiology, serological and CT imaging parameters, and arterial-phase gastric wall enhancement in CT scans were analyzed between the mild and severe PHG groups. No significant differences were observed in gender, age, etiology, serological markers, or MELD score between the two groups (all P > 0.05). However, spleen length, spleen volume, PLT/spleen length ratio, and PLT/spleen volume ratio differed significantly (P = 0.003, 0.011, 0.019, and 0.014, respectively). The optimal cutoff values for predicting PHG severity were 131.4 (AUC = 0.619), 613.29 (AUC = 0.596), 0.42 (AUC = 0.588), and 0.07 (AUC = 0.592), respectively. Patients with severe PHG demonstrated significantly greater arterial-phase gastric wall enhancement compared to mild PHG cases. Spleen length, spleen volume, and the platelet-to-spleen ratios presented predictive value for PHG severity, albeit with limited discriminative ability. Additionally, moderate-to-severe arterial phase gastric wall enhancement in CT scans may serve as a potential indicator of severe PHG.

Background:Noninvasive and cost-effective markers are needed to replace esophagogastroduodenoscopy in the screening for severe esophagogastric varices (EGVs) and portal hypertensive gastropathy (PHG). Objective:This study evaluated the performances of several commonly used fibrosis markers in assessing EGVs and PHG in cirrhosis patients. Design:Retrospective cohort study. Methods:A series of 323 patients with cirrhosis were consecutively enrolled and endoscopically followed up until variceal eradication was achieved. The Fibrosis-4 (FIB-4) score, albumin-bilirubin (ALBI) index, aspartate aminotransferase (AST)-to-alanine aminotransferase (ALT) ratio (AAR), AST-to-platelet ratio index (APRI), gamma-glutamyl transpeptidase-to-platelet ratio (GPR), and Lok score were calculated for each patient upon first admission. The performances of these markers in assessing EGVs and PHG were determined. Results:In the screening for clinically relevant esophageal varices (CREVs), none of the markers showed a significant ability to differentiate CREVs from non-CREVs (P > .05). The AAR (area under the curve (AUC): 0.581, sensitivity: 52.0%, specificity: 66.1%, P = .033) and the GPR (AUC = 0.596, sensitivity: 64.0%, specificity: 50.0%, P = .033) fairly differentiated clinically relevant gastric varices (CRGVs) from non-CRGVs patients. Moreover, no correlation was noted between PHG and CREVs (r = .016, P = .778) or between PHG and CRGVs (r = -.024, P = .666). Furthermore, no difference in the severity of PHG before and after variceal eradication was detected (P = .224). Conclusion:The studied markers revealed poor to no ability to assess EGVs or PHG. Hence, they cannot be used to substitute EGD in the screening for EGVs. Furthermore, endoscopic eradication of EGVs did not affect the severity of PHG.

The gut microbiota is essential for the development and regulation of the immune and intestinal homeostasis of the host. The present study aimed to investigate the composition, diversity and functional features of the microbiota in patients with liver cirrhosis. and healthy volunteers using high-throughput sequencing of the 16S rRNA gene, and evaluated inflammatory cell infiltration and the gut barrier in both the colonic mucosa and liver sections using histological analysis. Diversity and metagenome function of the gut microbiota significantly differed between healthy volunteers and patients with liver cirrhosis. Patients with cirrhosis showed decreased microbial richness, evenness, and diversity, with functional prediction indicating enrichment of phosphotransferase and membrane transport pathways, while amino acid and energy metabolism pathways were predominant in healthy controls. Furthermore, gut microbial dysbiosis associated with liver cirrhosis augmented inflammatory cell infiltration in the colonic mucosa and liver sections, impaired gut barrier function and enhanced intestinal permeability and bacterial translocation. The gut microbiota contributes to the pathophysiology of liver cirrhosis, which may impact prevention and treatment strategies for patients with liver cirrhosis.

Background and aims: Noninvasive assessments play a crucial role in ruling out high-risk esophageal varices (HREV) in cirrhotic patients. However, the value of sound touch elastography (STE) in predicting HREV has not been comprehensively investigated. Therefore, this study aimed to establish prediction models based on liver and spleen stiffness measurements obtained by STE and provide assessment strategies and cutoff values tailored for different clinical situations. Methods: This prospective study included cirrhotic patients who underwent esophagogastroduodenoscopy (EGD). Liver and spleen stiffness measurements by STE were performed within six months of EGD examination. Various prediction models and their corresponding cutoff values were established for different clinical situations, incorporating spleen diameter and laboratory parameters. Results: A total of 154 cirrhotic patients were included in the study and stratified into training (n = 119) and validation (n = 35) sets. Multivariable analysis revealed platelet, spleen diameter and spleen stiffness measurement as independent predictors of HREV. The model incorporating spleen stiffness measurement, platelet, and spleen diameter demonstrated superior performance in predicting HREV, yielding an area under the receiver operating characteristic curve (AUC) of 0.878 and 0.853 in the training set and validation set, respectively. Application of this model for screening cirrhotic patients could avoid EGDs in 39.7% (27/68) and 35.3% (6/17) of patients in the training and validation sets, respectively. Conclusions: Liver and spleen stiffness measurements obtained through STE are valuable for predicting HREV in cirrhotic patients. The developed prediction models and their corresponding cutoff values provide tailored solutions for various clinical situations, thereby effectively reducing the need for unnecessary endoscopies.

Liver fibrosis (LF) refers to the excessive deposition and abnormal distribution of the extracellular matrix (ECM) caused by acute or chronic liver injury, which affects the prognosis of liver diseases. Activated HSCs play a central role in LF through their ability to differentiate into myofibroblasts (MFBs) and secrete ECM. Intercellular communication within the liver is important for HSC activation and LF, whether in the initial or persistent stage. Hepatocytes (HCs), the most abundant cell type in the liver, are closely related to hepatic nutrition metabolism and detoxification. Moreover, HC damage is the initiating factor of LF, and interactions between HCs and HSCs may be the most critical event involved in the process of LF. This article reviews the intercellular communication between HCs and HSCs based on paracrine effects, extracellular vesicles, and inflammasomes, which is expected to lead to the development of effective antifibrotic strategies.

Liver fibrosis is a reversible pathophysiological condition characterized by excessive extracellular matrix deposition that can progress to cirrhosis and liver failure if left untreated. Taurine, a sulfur-containing amino acid, protects the liver from damage. However, the effects of taurine on liver fibrogenesis have not been completely elucidated. In this study, we used amino acid metabolomics, gene expression microanalysis, and single-cell RNA sequencing (scRNA-seq) to investigate the roles of taurine, formyl peptide receptor 2 (Fpr2), and proinflammatory macrophages in liver fibrosis in human fibrotic sections and two distinct mouse models of liver fibrosis. Taurine transporter SLC6A6 wild-type and knockout littermate models and critical element inhibitors were also used. We found that taurine levels were significantly reduced in both human and murine fibrotic sections and that exogenous taurine supplementation alleviated fibrosis via SLC6A6. Furthermore, gene expression microarray analysis and scRNA-seq analyses demonstrated that exogenous taurine mitigated liver fibrosis, mainly by regulating Fpr2-related macrophage status. WRW4-mediated inhibition of Fpr2 ameliorated M1 macrophage polarization and alleviated liver fibrosis. Additionally, exogenous taurine suppressed Fpr2-modulated macrophage M1 polarization and the production of associated proinflammatory cytokines by repressing NF-κBp65 phosphorylation; moreover, SLC6A6 deficiency or treatment of liver fibrosis mouse models with an NF-κB inhibitor, BAY, impaired this protective effect of taurine. Therefore, taurine exerts a protective effect against liver fibrosis by repressing Fpr2/NF-κBp65-regulated macrophage M1 polarization, highlighting its potential therapeutic agent.

Inflammatory Bowel Disease (IBD) is a complex disorder marked by ongoing inflammation in the gastrointestinal tract. Its intricate connection with the gut's microbial makeup is a significant aspect of its pathology. This detailed investigation delves into the interaction between IBD and gut microbiota, underscoring the crucial role of microbial imbalance in the development of this condition. A thorough comparative examination of the gut microbiota in individuals with and without IBD reveals notable differences. Special attention is given to Short-Chain Fatty Acids (SCFAs) for their influence on intestinal barrier function and immune regulation. The study also assesses the efficacy of microbial intervention strategies like probiotics, prebiotics, Fecal Microbiota Transplantation (FMT), and butyrate supplementation. These findings illuminate the potential of microbiome-focused treatments in reshaping gut flora, pointing to a new direction in IBD management. The paper concludes by proposing a holistic treatment approach that integrates dietary changes with novel therapeutic methods. This research significantly advances our understanding of the gut microbiome's function in IBD, offering novel insights and avenues for more effective management and treatment strategies.

Mucosal epithelial death is an essential pathological characteristic of portal hypertensive gastropathy (PHG). FADDosome can regulate mucosal homeostasis by controlling mitochondrial status and cell death. However, it remains ill-defined whether and how the FADDosome is involved in the epithelial death of PHG. The FADDosome formation, mitochondrial dysfunction, glycolysis process and NLRP3 inflammasome activation in PHG from both human sections and mouse models were investigated. NLRP3 wild-type (NLRP3-WT) and NLRP3 knockout (NLRP3-KO) littermate models, critical element inhibitors and cell experiments were utilized. The mechanism underlying FADDosome-regulated mitochondrial dysfunction and epithelial death in PHG was explored. Here, we found that FADD recruited caspase-8 and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) to form the FADDosome to promote Drp1-dependent mitochondrial fission and dysfunction in PHG. Also, FADDosome modulated NOX2 signaling to strengthen Drp1-dependent mitochondrial fission and alter glycolysis as well as enhance mitochondrial reactive oxygen species (mtROS) production. Moreover, due to the dysfunction of electron transport chain (ETC) and alteration of antioxidant enzymes activity, this altered glycolysis also contributed to mtROS production. Subsequently, the enhanced mtROS production induced NLRP3 inflammasome activation to result in the epithelial pyroptosis and mucosal injury in PHG. Thus, the FADDosome-regulated pathways may provide a potential therapeutic target for PHG.

BackgroundThis study aimed to evaluate the diagnostic abilities of the non-invasive serum biomarkers to predict liver fibrosis staging and evaluate the progress of hepatitis B.MethodsWe enrolled 433 patients with chronic HBV infection had complete medical data available for the study, who underwent percutaneous liver biopsy. The extent of fibrosis was assessed using the modified METAVIR score. The predictive values of the non-invasive serum biomarkers were evaluated by the areas under the receiving operator characteristics curves (AUROCs) with 95% confidence intervals.ResultsThe proportion of males with progressive stages of liver fibrosis was relatively larger, and the average age of patients with cirrhosis stages is older than the non-cirrhotic stages. We found PLT, GGT, ALP, TB, FIB4 and GPR to be significantly associated with liver fibrosis in our cohort. GGT showed a sensitivity of 71.4% and specificity of 76.7% in distinguishing cirrhosis (F4) from non-cirrhotic stages (F1-3), with an AUROC of 0.775 (95%CI 0.711-0.840).The AUROCs of the GPR in distinguishing cirrhosis (F4) from non-cirrhotic stages (F1-3) was 0.794 (95%CI 0.734-0.853), but it had a lower sensitivity of 59.2%. Additionally, GGT, FIB4, and GPR could differentiate advanced fibrosis (F3-4) from non-advanced fibrosis (F1-2) among individuals with chronic hepatitis B, with AUROCs of 0.723 (95%CI 0.668-0.777), 0.729 (95%CI 0.675-0.782), and 0.760 (95%CI: 0.709-0.811) respectively.ConclusionsGGT was a better biomarker to distinguish cirrhosis (F4) from non-cirrhotic stages (F1-3), while GPR was a better biomarker to identify advanced fibrosis (F3-4) and non-advanced fibrosis (F1-2) in patients with chronic hepatitis B.

INTRODUCTION:Hypoxia is an important characteristic of gastric mucosal diseases, and hypoxia-inducible factor-1α (HIF-1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF-1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified.OBJECTIVES:To evaluate the effects of hypoxia-induced HIF-1α on the development of gastric mucosal lesions.METHODS:Portal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)-induced mouse models in METTL3 mutant or NLRP3-deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed.RESULTS:HIF-1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3-dependent dynamin-related protein 1 (Drp1) N6-methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF-1α with PX-478, inhibiting Drp1-dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi-1) treatment or METTL3 mutation alleviated this process. Furthermore, HIF-1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF-1α-induced Drp1-dependent mitochondrial fission also enhanced glycolysis. Drp1-dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC.CONCLUSIONS:Under hypoxic conditions, HIF-1α enhances mitochondrial dysfunction via Drp1-dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.

Portal hypertensive gastropathy (PHG) is a serious complication and the most common gastric mucosal injury among patients afflicted with cirrhotic or non-cirrhotic portal hypertension (PHT). The pathogenesis of PHG is not completely understood and is likely to be complex. The roles of portal hypertension pressure, parenchymal liver disease, Child-Pugh classification, variceal pressure and Helicobacter pylori infection in the development of PHG are controversial. Splanchnic blood flow, the distribution of mucosal blood, vascular ectasia, local disturbances, inflammatory cell infiltration and increased cytokine production have also been examined to elucidate the underlying mechanisms of PHG. Moreover, various other elements, including prostaglandin E2 (PGE2), endothelin-1 (ET-1), tumour necrosis factor-α (TNF-α), Fas ligand (FasL)/Fas, nitric oxide (NO), oxygen free radicals and vascular endothelial growth factor (VEGF), have also been revealed to participate in the pathogenesis of PHG. This review provides an overview of the risk factors, classification and potential molecular processes involved in PHG, followed by a concise summary of our and other studies. This review aims to integrate information to deepen our understanding of the interplay between different signalling pathways involved the pathogenesis of PHG and provides insights into how these signalling pathways are regulated to control the development of PHG.

目的 研究细胞外信号调节激酶1和2（ERK1/2）通过调控NADPH氧化酶（Nox）和线粒体分裂在结肠炎中的作用。方法 3%葡聚糖硫酸钠（DSS）诱导小鼠急性结肠炎。将30只C57BL/6J小鼠用随机数表法分为6组：Control组、3%DSS组、1%二甲亚砜（DMSO）组、ERK1/2抑制剂（PD98059）组、3%DSS+1%DMSO组、3%DSS+PD98059组，每组5只。评估Control组和3%DSS组小鼠体重变化、结肠长度改变、疾病活动指数和结肠组织病理学改变，检测小鼠结肠黏膜ERK1/2、磷酸化（p）-ERK1/2、Nox1和Nox2表达水平。1%DMSO组、3%DSS+1%DMSO组给予腹腔注射1%DMSO;PD98059组、3%DSS+PD98059组小鼠给予腹腔注射PD98059。评估4组小鼠结肠组织病理学改变，检测Nox1、Nox2、动力相关蛋白1（DRP1）、p-DRP1-S616和p-DRP1-S637等线粒体分裂相关蛋白表达水平的改变。透射电镜观察Control组和3%DSS组小鼠结肠上皮细胞线粒体分裂情况。免疫荧光双染分析2组小鼠结肠黏膜中Nox2与线粒体外膜转位酶TOM复合体（TOMM20）共定位情况。分析2组小鼠结肠黏膜DRP1与Nox2 mRNA相对表达量的相关性。结果 与Control组相比，3%DSS组小鼠体重下降、结肠长度缩短、疾病活动指数增加和结肠组织病理学评分升高，结肠黏膜p-ERK1/2、Nox1和Nox2表达增加（P均＜0.05）。结肠炎小鼠结肠上皮细胞中的线粒体分裂增加，结肠黏膜的DRP1和Nox2共定位增加，两者mRNA相对表达呈正相关（r=0.678,P ＜0.05）。ERK1/2抑制剂PD98059改善结肠炎小鼠结肠组织病理学变化，并且下调结肠黏膜Nox1、Nox2、DRP1、p-DRP1-S616的表达。结论 抑制ERK1/2可能通过减轻Nox表达和线粒体分裂，改善结肠炎。

Background Berberine effectively alleviates non-alcoholic fatty liver disease (NAFLD). Nevertheless, the mechanism is incompletely comprehended. It has been reported that SIRT1 mediates lipid metabolism in liver and berberine promotes the expression of SIRT1 in hepatocytes. We hypothesized that SIRT1 mediated the effect of berberine on NAFLD. Methods The effects of berberine on NAFLD were evaluated in C57BL/6J mice fed a high-fat diet (HFD) and in mouse primary hepatocytes and cell lines exposed to palmitate. The change of fatty acid oxidation (FAO) and the activity of CPT1A were observed in HepG2 cells. Quantitative real-time polymerase chain reaction and Western blot were employed to observe the expression of SIRT1 and lipid metabolism-related molecules. The interaction between SIRT1 and CPT1A was investigated by using co-immunoprecipitation assay in HEK293T cells. Results Berberine treatment attenuated hepatic steatosis, reduced triglyceride (190.1 +/- 11.2 mu mol/g liver vs 113.6 +/- 7.6 mu mol/g liver, P < 0.001) and cholesterol (11.3 +/- 2.5 mu mol/g liver vs 6.3 +/- 0.4 mu mol/g liver, P < 0.001) concentration in the liver, and improved lipid and glucose metabolism disorders compared with the HFD group. The expression of SIRT1 was reduced in the liver of NAFLD patients and mouse models. Berberine increased the expression of SIRT1 and promoted the protein level of CPT1A and its activity in HepG2 cells. SIRT1 overexpression mimicked the effect of berberine on reducing triglyceride levels in HepG2 cells, whereas SIRT1 knock-down attenuated the effect of berberine. Mechanistically, berberine increased the expression of SIRT1. SIRT1 deacetylated CPT1A at the Lys675 site, which suppressed its ubiquitin-dependent degradation, thereby promoting FAO and alleviating non-alcoholic liver steatosis. Conclusions Berberine promoted SIRT1 deacetylation of CPT1A at the Lys675 site, which reduced the ubiquitin-dependent degradation of CPT1A and ameliorated non-alcoholic liver steatosis.

Background and Aims: Liver fibrosis is a chronic disease characterized by different etiological agents; dysregulated interactions between hepatocytes and HSCs contribute to this disease. β‐arrestin 1 (ARRB1) plays an important role in liver fibrosis; however, the effect of ARRB1 on the crosstalk between hepatocytes and HSCs in liver fibrosis is unknown. The aim of this study is to investigate how ARRB1 modulates hepatocyte and HSC activation during liver fibrosis. Approach and Results: Normal and fibrotic human liver and serum samples were obtained. CCl4‐induced liver fibrosis and methionine‐choline deficiency–induced NASH models were constructed. Primary hepatocytes and HSCs were isolated, and human hepatic LO2 and stellate LX2 cells were used. Small extracellular vesicles (EVs) were purified, and key proteins were identified. ARRB1 was up‐regulated in hepatocytes and associated with autophagic blockage in liver fibrosis. ARRB1 increased the release of hepatocyte‐derived small EVs by inhibiting multivesicular body lysosomal degradation and activating Rab27A, thereby activating HSCs. Proteomic analyses showed that mannan‐binding lectin serine protease 1 (MASP1) was enriched in hepatocyte‐derived small EVs and activated HSCs via p38 mitogen‐activated protein kinase (MAPK)/activating transcription factor 2 (ATF2) signaling. ARRB1 up‐regulated MASP1 expression in hepatocytes. MASP1 promoted liver fibrosis in mice. Clinically, MASP1 expression was increased in the serum and liver tissue of patients with liver fibrosis. Conclusions: ARRB1 up‐regulates the release of hepatocyte‐derived MASP1‐enriched small EVs by regulating the autophagic‐lysosomal/multivesicular body pathway and Rab27A. Hepatocyte‐derived MASP1 activates HSCs to promote liver fibrogenesis through p38 MAPK/ATF2 signaling. Thus, MASP1 is a pivotal therapeutic target in liver fibrosis.

Chronic hepatitis B (CHB) and its complications still have a major role in liver-related mortality. It has been indicated that hepatic iron and steatosis may influence liver fibrosis and carcinogenesis. The present study aimed to assess the liver iron and fat in patients with CHB by MRI in order to estimate the associations among liver iron, fat and the severity and progression of liver fibrosis. In the present retrospective study, consecutive patients with CHB examined from August 2018 to August 2020 were analyzed. Liver iron and fat content were assessed by MRI, which was measured as liver iron content (LIC) and proton density fat fraction (PDFF). A total of 340 patients were included in the current study. For LIC, the median value was 1.68 mg/g and elevated LIC was seen in 122 patients (35.9%). For liver fat content, the median value of PDFF was 3.1%, while only 15.0% of patients had liver steatosis (PDFF ≥5%). Age, total bilirubin and sex were independent predictive factors of liver iron overload [odds ratio (OR)=1.036, 1.005 and 8.834, respectively]. A higher platelet count (OR=1.005) and no portal hypertension (OR=0.381) independently predicted liver steatosis. The areas under the receiver operating characteristic curves of PDFF for the identification of liver cirrhosis estimated by different non-invasive tools ranged from 0.629 to 0.704. It was concluded that iron overload was common in patients with CHB, particularly in those with older age, male sex and high total bilirubin level, and liver steatosis was less common in CHB. Liver iron and fat content analyzed by MRI may contribute to the evaluation of the severity and progression of CHB.

Background and Purpose: The defective colonic mucus barrier is a feature of ulcerative colitis (UC) that enables increased bacterial contact with the epithelium, which triggers mucosal damage, and gastrin has been reported to be able to promote healing through the cholecystokinin 2 receptor (CCK2R) signaling to increase epithelial regeneration and protect against colonic injury. However, the role of gastrin in UC remains unclear. Experimental Approach: Colonic samples from human sections and mouse models using β-arrestin1 wild-type (β-arr1-WT) and β-arrestin1 knockout (β-arr1-KO) littermates, intestinal epithelial cells specific NF-κBp65 deletion (NF-κBp65) and wild-type (NF-κBp65) mice were analyzed. The mucosal injury, goblet cells status, MUC2 expression and bacteria penetration/colonisation were examined, and the effect of gastrin in colitis was also investigated. Key Results: We demonstrate that mucus barrier loss and bacterial colonisation of the crypts were observed in colitis, and exogenous gastrin could restore the mucus barrier, reduce bacterial colonisation of the colonic crypts and alleviate colitis via CCK2R. Furthermore, targeting CCK2R by YF476, β-arrestin1 (β-arr1) deletion or intestinal epithelial NF-κBp65 deficiency breached gastrin-mediated mucus barrier restoration and mucosal protection in colitis. Conclusion and Implications: These data demonstrate that gastrin alleviates mucus barrier loss and bacterial colonisation of the colonic crypts via CCK2R/β-arr1/NF-κBp65 signaling in colitis, and this network may be a potential therapeutic target for UC.

Liver cirrhosis is a form of liver fibrosis resulting from chronic hepatitis caused by various liver diseases, such as viral hepatitis, alcoholic liver damage, nonalcoholic steatohepatitis, autoimmune liver disease, and by parasitic diseases such as schistosomiasis. Liver fibrosis is the common pathological base and precursors of cirrhosis. Inflammation and disorders of lipid metabolism are key drivers in liver fibrosis. Studies have determined that parts of the arachidonic acid pathway, such as its metabolic enzymes and biologically active products, are hallmarks of inflammation, and that aberrant peroxisome proliferator-activated receptor gamma (PPARγ)-mediated regulation causes disorders of lipid metabolism. However, despite the ongoing research focus on delineating the mechanisms of liver fibrosis that underpin various chronic liver diseases, effective clinical treatments have yet to be developed. Berberine (BBR) is an isoquinoline alkaloid with multiple biological activities, such as anti-inflammatory, anti-bacterial, anti-cancer, and anti-hyperlipidemic activities. Many studies have also found that BBR acts via multiple pathways to alleviate liver fibrosis. Furthermore, the absorption of BBR is increased by nitroreductase-containing intestinal flora, and is strengthened via crosstalk with bile acid metabolism. This improves the oral bioavailability of BBR, thereby enhancing its clinical utility. The production of butyrate by intestinal anaerobic bacteria is dramatically increased by BBR, thereby amplifying butyrate-mediated alleviation of liver fibrosis. In this review, we discuss the effects of BBR on liver fibrosis and lipid metabolism, particularly the metabolism of arachidonic acid, and highlight the potential mechanisms by which BBR relieves liver fibrosis through lipid metabolism related and intestinal flora related pathways. We hope that this review will provide insights on the BBR-based treatment of liver cirrhosis and related research in this area, and we encourage further studies that increase the ability of BBR to enhance liver health.

Berberine (BBR) has been explored as a potential anti-liver fibrosis agent, but the underlying mechanisms are unknown. In the current study, we aimed to investigate the molecular mechanisms underlying the effect of BBR against liver fibrogenesis in thioacetamide (TAA) and carbon tetrachloride (CCl4) induced mouse liver fibrosis. In addition to i.p. injection with TAA or CCl4, mice in the treatment group received BBR intragastrically. Concurrently, combined with TAA and BBR treatment, mice in the inhibitor group were injected i.p. with ferrostatin-1 (Fer-1). Hepatic stellate cells (HSCs) were also used in the study. Our results showed that BBR obviously alleviated mouse liver fibrosis and restored mouse liver function; however, the pharmacological effects of BBR against liver fibrosis were significantly diminished by Fer-1 treatment. Mechanically, BBR impaired the autophagy-lysosome pathway (ALP) and increased cell reactive oxygen species (ROS) production in HSCs. ROS accelerated the breakdown of the iron-storage protein ferritin and sped up iron release from ferritin, which resulted in redox-active iron accumulation in HSCs. Lipid peroxidation and glutathione (GSH) depletion triggered by the Fenton reaction promoted ferroptosis and attenuated liver fibrosis. Furthermore, impaired autophagy enhanced BBR-mediated ferritin proteolysis to increase cellular ferrous overload via the ubiquitin-proteasome pathway (UPS) in HSCs and triggered HSC ferroptosis. Collectively, BBR alleviated liver fibrosis by inducing ferrous redox to activate ROS-mediated HSC ferroptosis. Our findings may be exploited clinically to provide a potential novel therapeutic strategy for liver fibrosis.