Targeting nuclear receptors for NASH/MASH:From bench to bedside

The onset of metabolic dysfunction-associated steatohepatitis(MASH)or non-alcoholic steatohepatitis(NASH)represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD).With no pharmacological treat-ment currently available for MASH/NASH,the race is on to develop drugs targeting multiple facets of hepatic metabolism,inflammation,and pro-fibrotic events,which are major drivers of MASH.Nuclear receptors(NRs)regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation.Ligands of NRs may include hormones,lipids,bile acids,and synthetic ligands,which upon binding to NRs regulate the transcriptional activities of target genes.NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH.This review aims to cover the current understanding of NRs,including nuclear hormone receptors,non-steroid hormone receptors,circadian NRs,and orphan NRs,which are currently undergoing clinical trials for MASH treatment,along with NRs that have shown promising results in preclinical studies.

Protective effects of cyclosporine and its analog NIM-811 in a murine model of hepatic ischemia-reperfusion injury

Background and aim:The liver is susceptible to ischemia-reperfusion injury(IRI)during hepatic surgery,when the vessels are compressed to control bleeding,or liver transplantation,when there is an obligate period of ischemia.The hallmark of IRI comprises mitochondrial dysfunction,which generates reactive oxygen species,and cell death through necrosis or apoptosis.Cyclosporine(CsA),which is a well-known immunosuppressive agent that inhibits calcineurin,has the additional effect of inhibiting the mito-chondrial permeability transition pore(mPTP),thereby,preventing mitochondrial swelling and injury.NIM-811,which is the nonimmunosuppressive analog of CsA,has a similar effect on the mPTP.In this study,we tested the effect of both agents on mitigating warm hepatic IRI in a murine model.Materials and methods:Before ischemic insult,the mice were administered with intraperitoneal normal saline(control);CsA at 2.5,10,or 25 mg/kg;or NIM-811 at 10 mg/kg.Thereafter,the mice were subjected to partial warm hepatic ischemia by selective pedicle clamping for 60 min,followed by 6 h of recovery after reperfusion.Serum alanine transaminase(ALT)was measured,and the liver tissue was examined histologically for the presence of apoptosis and the levels of inflammatory cytokines.Results:Compared with the control mice,the mice treated with 10 and 25 mg/kg of CsA and NIM-811 had significantly lower ALT levels(P<0.001,0.007,and 0.031,respectively).Moreover,the liver tissue showed reduced histological injury scores after treatment with CsA at 2.5,10,and 25 mg/kg and NIM-811(P=0.041,<0.001,0.003,and 0.043,respectively)and significant decrease in apoptosis after treatment with CsA at all doses(P=0.012,0.007,and<0.001,respectively).Levels of the pro-inflammatory cyto-kines,particularly interleukin(IL)-1β,IL-2,IL-4,IL-10,and keratinocyte chemoattractant/human growth-regulated oncogene significantly decreased in the mice treated with the highest dose of CsA(25 mg/kg)than those in the control mice.Conclusions:Premedication with CsA or NIM-811 mitigated hepatic IRI in mice,as evidenced by the decreased ALT and reduced injury on histology.These results have potential implications on mitigating IRI during liver transplantation and resection.

Genetic variants in the 6p21.3 region influence hepatitis B virus clearance and chronic hepatitis B risk in the Han Chinese population

Background and aim:A genome-wide association study has indicated the association of numerous genes in the 6p21.3 region with chronic hepatitis B virus(HBV)infection.In this study,we screened 12 representative single-nucleotide polymorphisms(SNPs)from the 6p21.3 region and investigated their association with the risk of chronic hepatitis B(CHB)to better understand the molecular etiology un-derlying CHB risk in the Han Chinese population.Methods:Between March 2021 and November 2022,we included 183 patients with CHB(case group)and 196 with natural HBV clearance(control group).Allele typing of the selected SNPs was performed using snapshot technology.The correlation between the 12 chosen SNPs and the risk of chronic HBV infection was examined using binary logistic regression analysis.Interacting genes of the variants were identified,and expression quantitative trait loci(eQTL)were analyzed using the 3DSNP database.Results:We validated 12 previously reported CHB susceptibility sites,including rs1419881 of tran-scription factor 19(TCF19),rs3130542 and rs2853953 of human leukocyte antigen(HLA)-C,rs652888 of euchromatic histone-lysine-methyltransferase 2(EHMT2),rs2856718,rs9276370,rs7756516,and rs7453920 of HLA-DQ,rs378352 of HLA-DOA,and rs3077,rs9277535,and rs9366816 of HLA-DP.Logistic regression analyses revealed that polymorphisms such as rs9276370,rs7756516,rs7453920,rs3077,rs9277535,and rs9366816 were positively correlated with natural HBV clearance in the dominant model.Conversely,rs3130542 and rs378352 were identified as risk factors for CHB.Haplotype analysis revealed that rs9276370,rs7756516,and rs7453920 in HLA-DQ were TTG and GCA haplotypes.Although the TTG haplotype was positively correlated with a higher risk of CHB,the GCA haplotype significantly influenced the natural clearance of HBV.Bioinformatics analysis demonstrated that rs378352,rs3077,and rs9366816 were located within enhancer states;rs3077 and rs9366816 overlapped with nine tran-scription factor-binding sites,whereas rs378352 altered five sequence motifs.Furthermore,eQTL analysis demonstrated the functional tendencies of eight statistically significant SNPs(rs3130542,rs9276370,rs7756516,rs7453920,rs378352,rs3077,rs9277535,and rs9366816).Conclusions:Genetic variations within the 6p21.3 region were associated with chronic HBV infection in the Han Chinese population in southern China.Furthermore,the GCA haplotype including rs9276370,rs7756516,and rs7453920 of HLA-DQ contributed significantly to natural HBV clearance,implying that multiple SNPs exert a cumulative allelic effect on HBV infection.

Role of the portal system in liver regeneration:From molecular mechanisms to clinical management

The liver has a strong regenerative capacity that ensures patient recovery after hepatectomy and liver transplantation.The portal system plays a crucial role in the dual blood supply to the liver,making it a significant factor in hepatic function.Several surgical strategies,such as portal vein ligation,associating liver partition and portal vein ligation for staged hepatectomy,and dual vein embolization,have high-lighted the portal system's importance in liver regeneration.Following hepatectomy or liver trans-plantation,the hemodynamic properties of the portal system change dramatically,triggering regeneration via shear stress and the induction of hypoxia.However,excessive portal hyperperfusion can harm the liver and negatively affect patient outcomes.Furthermore,as the importance of the gut-liver axis has gradually been revealed,the effect of metabolites and cytokines from gut microbes carried by portal blood on liver regeneration has been acknowledged.From these perspectives,this review outlines the molecular mechanisms of the portal system's role in liver regeneration and summarizes therapeutic strategies based on the portal system intervention to promote liver regeneration.

Viral hepatitis E:Clinical manifestations,treatment,and prevention

Hepatitis E is a globally distributed infection that varies in seroprevalence between developed and developing regions.In the less developed regions of Asia and Africa,a high seropositivity rate has been reported for hepatitis E virus(HEV)antibodies.Although acute hepatitis E is often self-limited and has a favorable prognosis,some populations experience severe manifestations,which may progress to liver failure.Moreover,some immunocompromised patients are at risk of developing chronic HEV infection and cirrhosis.Proactive screening,reducing misdiagnosis,improving patient management,timely anti-viral therapy for severe and chronic cases,and vaccination of high-risk groups are important measures to reduce the morbidity of hepatitis E.This review focused on the clinical presentation,management,and prevention of hepatitis E.

Physical activity and exercise in liver cancer

Sarcopenia and physical deconditioning are common complications in patients with liver cancer,which are frequently caused by insufficient physical activity and poor nutritional status,resulting in physical frailty and a significant impact on the patient's physical fitness.Notably,sarcopenia,frailty,and poor cardiopulmonary endurance have all been linked to higher mortality rates among patients with liver cancer.Exercise intervention significantly improves various health parameters in liver cancer patients,including metabolic syndrome,muscle wasting,cardiorespiratory endurance,health-related quality of life,and reduction in hepatic venous pressure gradient.However,the link between physical exercise and liver cancer is commonly overlooked.In this article,we will examine the impact of exercise on liver cancer and present the most recent evidence on the best types of exercise for various stages of liver cancer.This article also summarizes and discusses the molecular mechanisms that control metabolism and systemic immune function in tumors.In brief,physical exercise should be considered an important intervention in the prevention and treatment of liver cancer and its complications.

Predictive value of Th17 and Treg cells at baseline for HBsAg loss in chronic hepatitis B patients with low HBsAg quantification treated with pegylated interferon and nucleos(t)ide analogue

Background and aims:The primary goal of chronic hepatitis B(CHB)treatment is to reduce hepatitis B surface antigen(HBsAg).T helper 17(Th17)and regulatory T(Treg)cells are essential for the development of CHB.However,how Th17 and Treg cells contribute to HBsAg loss is still unknown.Therefore,this study aimed to search for the predictive value of Th17 and Treg cells for HBsAg loss in CHB patients with low HBsAg quantification.Methods:The study included 99 hepatitis B e antigen(HBeAg)-negative CHB patients who had completed a year of nucleos(t)ide analogue(NA)monotherapy and had received both NA and pegylated interferon(PEG-IFN)treatment for less than 96 weeks(96 wk).In the cured group,48 patients lost HBsAg within 48 wk,while 51 patients did not(uncured group).Blood samples and clinical data were collected for research.Results:During PEG-IFN and NA combination therapy,the proportion of Th17 cells in the cured group increased significantly,while the proportion of Treg cells in the uncured group increased.From 0 to 24 wk,the proportion of Th17 cells in the cured group was significantly higher than in the uncured group,while the opposite was true for Treg cells.Patients with alanine aminotransferase(ALT)2.5 upper limit of normal(ULN)at 12 wk had a higher proportion of Th17 cells and a lower proportion of Treg cells than those with ALT<2.5 ULN at 12 wk.Additionally,the proportion of Th17 cells is inversely associated with the level of HBsAg,whereas the level of Treg cells is positively related to HBsAg quantification.The clinical cure index,including age,HBsAg quantification,and the proportions of Th17 and Treg cells,had a higher area under the curve(0.957)for predicting HBsAg loss when compared to the proportions of Th17 and Treg cells and HBsAg quantification alone.Conclusions:Combined with quantification of HBsAg,the proportions of Th17 cells and Treg cells at baseline can be used as good predictors of HBsAg loss in patients with low HBsAg quantification treated with NA and PEG-IFN.

New insights in the pathogenesis of alcohol-related liver disease:The metabolic,immunologic,and neurologic pathways

Alcohol-related liver disease(ALD)became an important health issue worldwide.Following chronic alcohol consumption,the development of ALD might be caused by metabolic and immunologic factors,such as reactive oxygen species(ROS)and pro-inflammatory cytokines.For example,hepatic cytochrome P4502E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure.In addition,damage-and pathogen-associated molecular patterns stimulate their specific receptors in nonparenchymal cells,including Kupffer cells,hepatic stellate cells(HSCs),and lymphocytes,which result in hepatocyte death and infiltration of pro-inflammatory cells(e.g.,neutrophils and macrophages)in the liver.Moreover,our studies have suggested the novel involvement of neurologic signaling pathways(e.g.,endocannabinoid and glutamate)through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis.Additionally,agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis.Furthermore,organ-crosstalk has emerged as a critical issue in ALD.Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut,leading to endotoxin leakage into the portal circulation,or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver.In summary,this review addresses multiple pathogeneses of ALD,provides novel neurologic signaling pathways,and emphasizes the importance of organ-crosstalk in the development of ALD.

Molecular mechanisms of autophagy and implications in liver diseases

Autophagy is a highly conserved process in which cytosolic contents are degraded by the lysosome,which plays an important role in energy and nutrient balance,and protein or organelle quality control.The liver is the most important organ for metabolism.Studies to date have revealed a significant role of autophagy in the maintenance of liver homeostasis under basal and stressed conditions,and the impairment of autophagy has been closely linked to various liver diseases.Therefore,a comprehensive understanding of the roles of autophagy in liver diseases may help in the development of therapeutic strategies via targeting autophagy.In this review,we will summarize the latest understanding of the molecular mechanisms of autophagy and systematically discuss its implications in various liver diseases,including alcohol-related liver disease,non-alcoholic fatty liver disease,viral hepatitis,hepatocellular carcinoma,and acetaminophen-induced liver injury.

The contributions of bacteria metabolites to the development of hepatic encephalopathy

Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma.HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels.Thus,the brain is exposed to intestinal-derived toxic substances.Moreover,the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation.This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE.Together,the significance of the gut-liver-brain axis in human health warrants attention.This review paper focuses on the roles of bacteria metabolites,mainly ammonia and bile acids(BAs)as well as BA receptors in HE.The literature search conducted for this review included searches for phrases such as BA receptors,BAs,ammonia,farnesoid X receptor(FXR),G protein-coupled bile acid receptor 1(GPBAR1 or TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy.PubMed,as well as Google Scholar,was the search engines used to find relevant publications.

Current and emerging therapies for alcohol-associated hepatitis

Alcohol-related liver disease(ALD)encompasses a spectrum of diseases caused by excessive alcohol consumption.ALD includes hepatic steatosis,steatohepatitis,variable degrees of fibrosis,cirrhosis,and alcohol-associated hepatitis(AH),the latter being the most severe acute form of the disease.Severe AH is associated with high mortality(reaching up to 30%e50%)at 90 days.The cornerstone of ALD,and particularly AH,treatment continues to be abstinence,accompanied by support measures such as nutritional supplementation and management of alcohol withdrawal syndrome(AWS).In severe AH with model for end-stage liver disease(MELD)score21,corticosteroids can be used,especially MELD score between 25 and 39,where the highest benefit is achieved.Other key aspects of treatment include the early identification of infections and their associated management and the proper identification of potential candidates for liver transplantation.The development of new therapies based on the pathophysiology and mechanisms of liver injury are underway.This includes the modulation and management of the innate immune response,gut dysbiosis,bacterial translocation,and bacteria-derived products from the intestine.These hold promise for the future of AH treatment.

Progress on clinical prognosis assessment in liver failure

Liver failure is a group of clinical syndromes with a mortality rate of>50%.The accurate evaluation of severity in patients with liver failure has been a meaningful and hot topic in clinical research and an important guide for liver transplantation.Numerous prognosis studies have emerged in recent years with high accuracy and adequate validity.Nonetheless,different models utilize distinct parameters and have unequal efficiencies,leading to a specific value and unique application situations for each model.This review focused on the progress in recent prognostic studies including the model for end-stage liver disease,sequential organ failure assessment and its derivative models,the Chinese Group on the Study of Severe Hepatitis B Acute-on-Chronic Liver Failure,the Tongji prognostic predictor model,and other emerging prognostic models and predictors.This review aims to assist clinicians understand the framework of recent models and choose the appropriate model and treatment.

Effects of Bacillus Calmette-Guerin on immunometabolism,microbiome and liver diseases

Metabolic diseases have overtaken infectious diseases as the most serious public health issue and economic burden in most countries.Moreover,metabolic diseases increase the risk of having infectious diseases.The treatment of metabolic disease may require a long-term strategy of taking multiple medications,which can be costly and have side effects.Attempts to expand the therapeutic use of vaccination to prevent or treat metabolic diseases have attracted significant interest.A growing body of evidence indicates that Bacillus Calmette-Guerin(BCG)offers protection against non-infectious diseases.The non-specific effects of BCG occur likely due to the induction of trained immunity.In this regard,understanding how BCG influences the development of chronic metabolic health including liver diseases would be important.This review focuses on research on BCG,the constellation of disorders associated with metabolic health issues including liver diseases and diabetes as well as how BCG affects the gut microbiome,immunity,and metabolism.

Synergistic impacts of rifampicin and doxorubicin against thioacetamide-induced hepatocellular carcinoma in rats

Background and aims:Combination therapy is a promising new strategy that has been proposed to increase the efficacy of cancer treatment.We aimed to investigate the anti-cancer activity of rifampicin monotherapy and its combination with doxorubicin against hepatocellular carcinoma(HCC).Materials and methods:The in vitro half maximal inhibitory concentration(IC50)and selectivity index(SI)of the drugs under investigation against HepG2 and human lung fibroblast(WI38)cell lines were determined.For the in vivo experiment,male Sprague-Dawley albino rats were injected with thioacetamide at 200 mg/kg twice a week for 90 days;HCC development was confirmed histopathologically.Following HCC induction,the rats were treated with intraperitoneal doxorubicin,rifampicin,or their combination for 45 or 90 days.After sacrifice,the livers were examined histopathologically.The levels of aminotransferases,albumin,bilirubin,malondialdehyde,superoxide dismutase(SOD),catalase(CAT),total antioxidant capacity(TAC),and nitric oxide were measured by spectrophotometry.Alphafetoprotein,cancer antigen 19-9,tumor necrosis factor-alpha,interleukin-6,Bcl-2-associated X protein,caspase 3,caspase 8,and p53 were estimated using ELISA.Results:In vitro,the combination of doxorubicin and rifampicin showed the highest SI of 3.43.In vivo,among the measured markers,the levels of TAC,CAT,SOD,and p53 decreased(P<0.001)and the rest of the measured marker levels increased(P<0.001)in the HCC-bearing rats;after treatment in all groups,all these changes improved toward normal in a time-dependent manner.The combination of doxorubicin and rifampicin optimized the effects of the two individual drugs and exerted the best antioxidant effects.Conclusions:In general,compared with rifampicin or doxorubicin alone,combination therapy has favorable outcomes.Based on our results,the combination of rifampicin and doxorubicin might be applicable for HCC chemotherapy.

Integrative analysis of bulk and single-cell RNA sequencing data reveals distinct subtypes of MAFLD based on N1-methyladenosine regulator expression

Background:Metabolic dysfunction-associated fatty liver disease(MAFLD)is now the most prevalent chronic liver disease worldwide,with an increasing incidence rate.MAFLD is a heterogeneous disease that can have a low or high-risk profile for developing severe liver disease in its natural course.Recent evidence has highlighted the critical role of RNA methylation modification in the pathogenesis of various liver diseases.However,it remains unclear whether the RNA N1-methyladenosine(m1A)modification of immune cells could potentially contribute to the pathogenesis and heterogeneity of MAFLD.Materials and methods:To address this issue,we conducted an integrated bioinformatics analysis of MAFLD bulk and single-cell RNA sequencing(scRNA-seq)data to pinpoint m1A regulators in the network.This was followed by a description of the immune landscape,pathway enrichment analysis,and molecular subtyping.Results:The expression patterns of m1A regulatory genes stratify MAFLD into two molecular subtypes,Cluster 1 and Cluster 2.These subtypes demonstrate different immune cell infiltration with distinct inflammation characteristics,which suggest different immune-inflammatory responses in the liver.Notably,Cluster 2 is associated with pro-inflammation and may be more likely to lead to progressive stages of MAFLD.Through intersection analysis of weighted gene co-expression network analysis(WGCNA)and m1A regulatory genes,three true hub genes(ALKBH1,YTHDC1,and YTHDF3)were identified,all of which were strongly correlated with infiltrating immune cells.The specific signaling pathways involved in the three core genes were derived from genomic variation analysis.Furthermore,scRNA-seq data from 33,168 cells from six liver samples identified 26 cell clusters and eight cell types,with endothelial cells,macrophages,and monocytes showing the most significant differences between MAFLD and normal controls.The cell-cell communication network between immune cells and nonparenchymal cells was extremely sophisticated and changed significantly in MAFLD.Conclusions:In summary,these findings demonstrate the involvement of m1A in MAFLD heterogeneity and emphasize the crucial role of m1A modulation of immune cells in regulating inflammation in MAFLD.These results may suggest potential therapeutic strategies for MAFLD.

Immunotherapy as adjuvant therapy for a patient with adenosquamous carcinoma of the intrahepatic bile duct:A case report and literature review

Adenosquamous carcinoma(ASC)is a rare histological type of intrahepatic cholangiocarcinoma,which includes both adenocarcinoma and squamous cell carcinoma.The clinical features,physical examination,routine laboratory tests,and imaging examinations of patients with ASC are nonspecific.ASC is easily misdiagnosed as hepatocellular carcinoma,and patients with ASC always have a poor prognosis.This study reports a patient with ASC who was diagnosed based on pathological results,underwent surgical resection,and received postoperative chemotherapy(gemcitabine plus cisplatin)combined with immunotherapy(sintilimab).During the 1-year follow-up,the patient was in good condition,and no signs of cancer recurrence were noted.This case highlights that surgical resection and chemotherapy combined with immunotherapy may be feasible for patients with ASC.

COVID-19 associated liver injury:An updated review on the mechanisms and management of risk groups

Coronavirus disease 2019(COVID-19)has been associated with various liver injury cases worldwide.To date,the prevalence,mechanism,clinical manifestations,diagnosis,and outcomes of COVID-19-induced liver injury in various at-risk groups are not well defined.Liver injury may arise in the prevention and treatment of COVID-19 from direct causes such as viral infection and indirect causes such as systemic inflammation,hypoxic changes,and drugs that exacerbate any pre-existing liver disease.Studies have found that patients with underlying liver disease are at higher risk of COVID-19-induced liver injury.Certain condition of cardiopulmonary and metabolic diseases and vulnerable stages in lifespan may also involve in the development of COVID-19-induced liver injury.This review summarized studies of COVID-19-induced liver injury in different at-risk groups regarding their clinical characteristics,parameters,and correlations of the severity with these indicators and signs as well as potential treatment suggestions,to increase attention to physiological and pathological conditions and continue liver function monitoring as they can help in strengthening early supportive treatment and reducing the incidence of adverse outcomes.

Heterogeneous population of macrophages in the development of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)is characterized by a spectrum of hepatic diseases,including fatty liver,non-alcoholic steatohepatitis,cirrhosis,and hepatocellular carcinoma.NAFLD is a hepatic manifestation of metabolic syndrome and has become the leading cause of liver transplantation,necessitating an in-depth understanding of its underlying pathogenic mechanisms and the identification of viable drug targets.Although fatty liver is benign and does not exert marked liver damage or inflammation,NAFLD progression involves inflammatory processes facilitated by immune cells.Macrophages and monocytes constitute the pool of innate immune cells that contribute to NAFLD development in association with other cell types,such as neutrophils,T cells,and natural killer cells.The concept that macrophages contribute to the inflammatory processes in NAFLD development has long been debated;however,the remarkable advances in experimental techniques have rapidly uncovered new subpopulations of macrophages and monocytes,whose functions need to be comprehensively elucidated.The current review focuses on the recent expansion of our knowledge of the heterogeneous population of macrophages crucially involved in NAFLD development.In addition,the present paper discusses ongoing efforts to target macrophages and inflammatory processes to develop optimal therapeutic agents against non-alcoholic steatohepatitis.

Microbial transformations of bile acids and their receptors in the regulation of metabolic dysfunction-associated steatotic liver disease

Bile acids(BAs)play important roles in the digestion of dietary fats and molecular signal transduction,and modulation of the BA composition usually affects the progression of metabolic diseases.While the liver produces primary BAs,the gut microbiota modifies these products into various forms that greatly increase their diversity and biological functions.Mechanistically,BAs can regulate their own metabolism and transport as well as other key aspects of metabolic processes via dedicated BA receptors.Disruption of BA transport and homeostasis leads to the progression of liver diseases,including metabolic dysfunction-associated steatotic liver disease(MASLD)and hepatocellular carcinoma(HCC).Here,we summarize the microbial transformations of BAs and their downstream signaling in the development of metabolic diseases and present new insights into novel therapeutic strategies targeting BA pathways that may contribute to these diseases.

Autophagy modulates physiologic and adaptive response in the liver

Autophagy is a physiological process that is ubiquitous and essential to the disposal or recycling of damaged cellular organelles and misfolded proteins to maintain organ homeostasis and survival.Its importance in the regulation of liver function in normal and pathological conditions is increasingly recognized.This review summarizes how autophagy regulates epithelial cell-and non-epithelial cellspecific function in the liver and how it differentially participates in hepatic homeostasis,hepatic injury response to stress-induced liver damage such as cholestasis,sepsis,non-alcoholic and alcohol-associated liver disease,viral hepatitis,hepatic fibrosis,hepatocellular and cholangiocellular carcinoma,and aging.Autophagy-based interventional studies for liver diseases that are currently registered in clinicatrials.gov are summarized.Given the broad and multidirectional autophagy response in the liver,a more refined understanding of the liver cell-specific autophagy activities in a context-dependent manner is necessary。