BACKGROUND AND AIMS:Pradefovir mesylate is a novel liver-targeting prodrug of adefovir developed using HepDirect technology. We report that the phase 3 trial is to compare the efficacy and safety of pradefovir versus tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB). APPROACH AND RESULTS:This ongoing randomized, double-blind, non-inferiority, phase 3 study was conducted at 58 sites in China. Patients with CHB were randomly assigned (2:1) to receive either 45 mg daily pradefovir or 300 mg daily TDF with a matching placebo. The primary efficacy endpoint was defined as the proportion of patients whose HBV DNA level was <29 IU/mL at week 48. All participants who received at least 1 dose of the study drug were included in efficacy and safety analyses with pre-specified renal and bone endpoints at week 96. A total of 1170 patients were screened during the study, and 908 patients received the study drug. At week 48, viral suppression (HBV DNA <29 IU/mL) rates of pradefovir were non-inferior to TDF in HBeAg-positive [-1.8% (95% CI: -9.7 to 6.1)] and HBeAg-negative [2.6% (95% CI: -5.1 to 10.3)] patients, using a non-inferiority margin of -12%. By week 96, HBeAg-positive patients showed significantly greater HBsAg decline (≥1 log 10 IU/mL) with pradefovir (39.3% vs. 29.9%). Pradefovir demonstrated a more favorable safety profile at week 96, including significantly fewer drug-related adverse events (58.6% vs. 71.9%), improved bone/renal safety, and a lower incidence of elevated creatine phosphokinase-MB. CONCLUSIONS:Pradefovir should be a highly recommended treatment option for adult patients with CHB.
Chronic hepatitis B virus (HBV) infection remains a major burden. The “Hot Wave Project,” a hospital-wide initiative launched in 2022, aims to enhance HBV care by integrating patient education with systematic screening, referral, diagnosis, treatment, and follow-up. We conducted a comparative analysis of hospital-wide HBV care metrics between 2021 (preintervention) and 2024 (postintervention). An interrupted time series (ITS) analysis was conducted on monthly data to evaluate the causal impact of the intervention. A decision-analytic Markov model was used to simulate the cost-effectiveness and epidemiological impact of the project on a hypothetical cohort of one million patients. From 2021 to 2024, the HBsAg screening rate hospital-wide increased from 11.75
BACKGROUND:Chronic hepatitis B (CHB) virus infection is the leading cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogs (NAs) effectively suppress HBV replication, but residual HCC risk remains in treated patients, highlighting the need for reliable risk stratification tools. Existing prediction models rely heavily on age and liver function parameters and often overlook hepatitis B surface antigen (HBsAg) quantification, a key marker closely tied to HBV-related HCC, resulting in inadequate clinical predictive accuracy. METHODS:To address this gap, we developed the novel HBsAg-HCC Score using a two-cohort design: retrospective training (1190 NA-treated CHB patients) with Cox regression to identify independent HCC risk factors, followed by validation in an independent prospective cohort (506 patients). Its performance was compared with three established tools (PAGE-B, mPAGE-B, aMAP). RESULTS:Five independent HCC risk factors were identified: higher HBsAg levels, older age, male sex, hypoproteinaemia, and elevated APRI. The HBsAg-HCC Score derived from these factors showed strong predictive power: 3-/5-/7-year AUCs of 0.867/0.872/0.871 in the training cohort (significantly outperforming PAGE-B, mPAGE-B, aMAP) and 0.784/0.780/0.777 in the validation cohort. Internal and external cross-validation confirmed its stability and reliability. CONCLUSIONS:By incorporating HBsAg quantification, a virus-specific marker often missing from conventional models, the HBsAg-HCC Score offers a more comprehensive and accurate approach to HCC risk stratification in NAs-experienced CHB patients, addressing a critical limitation of existing models directly.
BACKGROUND & AIMS:Lgr5+ hepatocytes constitute a specialized lineage central to nutrient and xenobiotic metabolism. In metabolic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH), lipid accumulation occurs throughout the liver; however, zone-specific hepatocyte responses to metabolic stress remain poorly understood. Here, we investigated the role of the SWI/SNF subunit DPF2 in Lgr5+ hepatocytes and its contribution to hepatic metabolic homeostasis and radiation induced liver damage (RILD). METHODS:Transgenic C57BL/6J mice were fed fructose-palmitate-cholesterol or choline-deficient amino acid-defined and high fat diets under pathogen-free conditions to induce MASLD/MASH. Multi-modal analyses - including single-cell RNA sequencing, spatial transcriptomics, ATAC sequencing, CUT&Tag, and CUT&RUN - were used to define the epigenetic and transcriptional regulation of cytochrome P450 family 2 subfamily (Cyp2) genes in Lgr5+ hepatocytes. Functional interventions included pharmacological all-trans retinoic acid (atRA) supplementation, CYP2 inhibition, and gene delivery via adeno-associated viruses or hydrodynamic tail vein injection. RESULTS:Dpf2 deletion in Lgr5+ hepatocytes disrupted liver metabolic homeostasis, resulting in marked hepatic lipid accumulation and RILD. DPF2 loss increased chromatin accessibility and histone activation marks at Cyp2 promoters, driving CYP2 enzyme expression and excessive atRA catabolism. The resulting reduction in atRA decreased AMPK phosphorylation throughout the liver. Restoration of atRA rescued AMPK activity and ameliorated MASLD severity, highlighting a metabolite-mediated, non-cell-autonomous mechanism linking a small hepatocyte subset to whole-liver metabolic regulation. CONCLUSIONS:DPF2 in Lgr5+ hepatocytes is a critical regulator of hepatic metabolism, acting via the CYP2-atRA-AMPK axis. These findings reveal the mechanistic basis for zone-specific metabolic control in the liver and identify atRA homeostasis as a potential therapeutic target for MASLD and MASH. IMPACT AND IMPLICATIONS:This study dissects chromatin regulation across spatially distinct hepatocyte populations and demonstrates that DPF2 activity within a rare Lgr5+ hepatocyte subset is sufficient to drive metabolic reprogramming and MASLD progression. These findings have important implications for both liver research and clinical practice, highlighting how liver-wide genetic manipulations or bulk omics analyses may obscure key disease-driving mechanisms confined to spatially restricted cell populations. From a translational perspective, our data suggest that targeting chromatin regulators or retinoid metabolic pathways may provide effective and safe therapeutic benefit; notably, systemic atRA administration can still confer robust protection or prevention at the whole-liver level. Although supported by rigorous mouse genetics, high-resolution transcriptomics, and validation in human liver tissues, clinical translation will require confirmation in larger human cohorts and carefully designed patient studies.
BACKGROUND:Concomitant metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in patients with chronic hepatitis B (CHB), yet its impact on liver-related outcomes remains controversial. Although the stimulator of interferon genes (STING) pathway is pivotal in innate immunity, its involvement in CHB-MASLD comorbidity is undefined. OBJECTIVE:We aimed to elucidate the role and mechanism of macrophage STING in CHB-MASLD comorbidity. DESIGN:Human and mouse liver tissues were used to assess STING expression levels. Myeloid-specific STING knockout and hepatocyte-specific STING knock-in mice were used to explore the effects of STING in comorbidity. Tohoku Hospital Pediatrics (THP)-1 and HepG2.2.15/HepG2-NTCP co-cultured cells were stimulated with palmitic acid (PA) for 12 hours in vitro for mechanism research. Markers for STING, autophagy and endoplasmic reticulum stress (ERS) were assessed using western blot analysis, immunohistochemistry and immunofluorescence assays. The liver organoids were used for validation. RESULTS:CHB-MASLD comorbidity in mice decreased HBV replication but accelerated liver inflammation and fibrosis, linked to aberrant STING upregulation in macrophages. HBV synergised with lipotoxicity to disrupt Rab7 expression and function in macrophages, impairing STING degradation via autophagic-lysosomal and endosomal-lysosomal pathways. Pathological STING accumulation had dual effects: cytosolic STING enhanced antiviral activity (TANK-binding kinase 1-interferon regulatory factor 3-interferon beta) and promoted inflammation (nuclear factor kappa-B/NOD-like receptor family pyrin domain-containing 3 (NLRP3)). Extracellular vesicles transported STING to hepatocytes, triggering ERS (PKR-like endoplasmic reticulum kinase (PERK)-C/EBP homologous protein (CHOP)), further activating NLRP3 and exacerbating injury. Therapeutically, restoring Rab7 facilitated STING degradation, attenuating pathology. CONCLUSIONS:In CHB-MASLD comorbidity, impaired Rab7 function leads to aberrant STING accumulation in macrophages, suppressing HBV replication but paradoxically accelerating liver disease progression. Targeting Rab7 to degrade excessive STING represents a novel therapeutic strategy.
BACKGROUND AND AIMS:Immune-mediated bile duct injury is the primary histological feature of autoimmune cholestatic liver diseases. Macrophages, the most abundant immune cell population in the liver, have been postulated to play a critical role in biliary repair. However, it is unclear whether activated macrophages interact with injured biliary epithelial cells. METHODS:We evaluated the expression of insulin-like growth factor-binding protein 4 (IGFBP4) in primary monocytes, MDMΦ, serum, and liver tissue sections from a total of 292 samples from PBC, PSC, and healthy controls using RNA-sequencing, ELISA, and immunohistochemistry analysis. The signal pathways involved in the effect of IGFBP4 in human intrahepatic biliary epithelial cells were examined by phospho-kinase arrays. RESULTS:Herein we demonstrate a role for insulin-like growth factor binding protein 4 (IGFBP4) in the interaction of macrophages and biliary cells. Importantly, the serum levels of IGFBP4 are significantly increased in PBC and negatively correlate with bilirubin levels. Furthermore, immunohistochemistry revealed an increase in IGFBP4 positive cells located not only in the periductal area but also around the portal tract in the PBC liver. In vitro study indicated that IGFBP4 protected biliary cells from bile salt-induced cell injury and promoted biliary cell proliferation, which was associated with reduced expression of the bile acid receptor TGR5, bile acid efflux transporter SLCO3A1, and activation of the GSK-3β/β-catenin signalling pathway. CONCLUSIONS:These data highlight that IGFBP4 not only serves as a potential biomarker for PBC but also plays a protective role against bile duct injury.
Liver fibrosis is characterized by deposition of excessive extracellular matrix (ECM). The major source of ECM is activated hepatic stellate cells (HSCs). NAT10 is the only known acetyltransferase catalyzing ac4C RNA modification. The purpose of this study is to explore the role of NAT10 acting as ac4C acetyltransferase during HSC activation. NAT10 was detected in fibrotic liver tissues from S. japonicum infected mice with immunohistochemistry and TGF-β1 stimulated LX-2 human HSC cells with Western blot and immunofluorescent staining. NAT10 was inhibited with specific siRNA in LX-2 cells to detect HSC activation molecular marker with Western blot, cell motility with Transwell assay, cell proliferation with CCK8 assay. ac4C modification was assessed in TGF-β1 stimulated LX-2 cells with immunofluorescent staining. ac4C chemical sequencing and transcriptomic sequencing analysis were performed to analyze ac4C modified genes regulated by NAT10 in TGF-β1 stimulated LX-2 cells. Possible target genes regulated by NAT10 were determined using qPCR, RIP-qPCR, RNA stability assay, and were further verified using primary hepatic stellate cells from mice and using analysis of GEO datasets. NAT10 increases in S. japonicum infected mice liver and activated HSCs. NAT10 inhibition suppresses HSC activation. NAT10 is correlated with TGFB1 and COL1A1 expression in activated HSCs. NAT10 promotes the ac4C modification and stability of TGFB1 and COL1A1 mRNA, thus enhancing their protein expression. NAT10 functions as an ac4C acetyltransferase and forms a positive feedback with TGF-β1 in HSCs, thereby modulating the TGF-β1-ac4C-COL1A1 axis, to promote HSC activation and liver fibrosis progression.
BACKGROUND AND AIMS:Accurate N-staging of intrahepatic cholangiocarcinoma (iCCA) remains challenging using noninvasive approaches. We aimed to develop a model to refine lymph node (LN) involvement stratification and inform therapeutic consideration. APPROACH AND RESULTS:This study enrolled a discovery cohort (n=682), an internal test cohort from the FU-iCCA (n=204), and an external multicenter cohort (n=88) for model development, and a neoadjuvant therapy (NAT) cohort (n=145) for therapeutic evaluation of the model. A SwinU-CliRad framework was constructed by integrating Swin UNEt TRansformers (Swin UNETR)-based magnetic resonance imaging-derived outputs of LN involvement with clinicoradiological features. Correlations between SwinU outputs and tumor multi-omics profiles were explored. The SwinU-CliRad model achieved areas under the curve (AUCs) of 0.932, 0.867, and 0.888 in LN risk stratification, and outperformed radiologist-based assessments by correcting more misclassifications than it introduced across the discovery, internal, and external test cohorts (18.8% vs. 7.3%, 18.1% vs. 4.9%, and 17.0% vs. 5.7%), respectively. In the NAT cohort, patients classified as high LN-involved risk by the SwinU-CliRad exhibited lower residual viable tumor rates than those with low LN-involved risk, with higher rates of pathological complete response (12.0% vs. 4.2%) and major pathological response (14.0% vs. 8.4%). SwinU outputs were associated with KRAS mutations, MUC5AC overexpression, and the large-duct histological subtype. Single-cell RNA sequencing analysis linked LN involvement to an immune-suppressive stroma tumor microenvironment. CONCLUSIONS:The SwinU-CliRad model can serve as a biologically interpretable tool for LN risk stratification in iCCA surgical candidates, with high-risk patients identified by the model potentially deriving benefit from NAT.
Tamoxifen (TAM) is a widely used estrogen receptor modulator for breast cancer treatment. However, TAM exhibits significant hepatotoxicity in the clinic, affecting nearly 50% of patients and thereby limiting its clinical utility. The specific mechanisms underlying TAM-induced liver injury remain poorly understood. In this study, we elucidated the mechanistic role of the gut microbiota in the hepatotoxicity associated with TAM. TAM administration induced substantial liver injury and gut microbiota dysbiosis in mice, characterized by an increased abundance of Escherichia and a reduction in Lachnospiraceae NK4A136 group. These microbial shifts resulted in decreased levels of total fecal bile acids (BA), particularly hyodeoxycholic acid (HDCA), which was inversely correlated with TAM-induced liver injury. Additionally, TAM disrupted BA homeostasis by enhancing intestinal Farnesoid X receptor (FXR) activity and concurrently stimulating hepatic BA synthesis through an alternative nonintestinal FXR mechanism. Notably, gut microbiota depletion reversed these effects, demonstrating the critical role of the microbiota in modulating the gut‒liver FXR axis in TAM-induced liver injury. Fecal microbiota transplantation (FMT) further confirmed that TAM directly stimulated hepatic BA synthesis through a microbiota-dependent mechanism. The disruption of the gut‒liver BA‒FXR axis impaired enterohepatic BA circulation, contributing to the liver toxicity associated with TAM administration. Importantly, HDCA supplementation restored the gut‒liver BA‒FXR axis and alleviated TAM-induced liver injury. These findings highlight the intricate relationship between TAM, gut microbiota, and BA metabolism, suggesting that targeting the gut-liver FXR axis with HDCA may serve as a promising therapeutic strategy for alleviating TAM-associated liver injury.
Primary biliary cholangitis (PBC) is a chronic, cholestatic disease with a female predominance and a long disease duration. The pathogenesis of PBC is still unclear; however, genetic, epigenetic, and environmental factors, alongside immune dysregulation, seem to lead to a dysfunction of the biliary ‘bicarbonate umbrella’ and increased biliary epithelial cells apoptosis. Ursodeoxycholic acid (UDCA) has been the treatment of choice for PBC since its approval back in 1994; however, a percentage varying from 15-40% of all patients fail to achieve biochemical response or alkaline phosphatase normalization. Obeticholic acid, though promising at first, failed to show benefit after long-term use and was retracted from the market. Two peroxisome proliferator–activated receptor agonists (PPARs) have recently been approved for use in patients with PBC, showing biochemical response in non-responders and improvement of pruritus. However, a substantial percentage of patients fail to achieve serum alkaline phosphatase and bilirubin normalization; as a result, many drugs with different mechanisms of action are in phase 2 or 3 trials. The aim of this review is to present available data regarding PBC treatment and explain the pathogenetic pathway each one targets.
BACKGROUND:There is currently no pharmacological therapy proven to alter the natural course of primary sclerosing cholangitis (PSC). The PRIMIS trial evaluated the efficacy and harms of the farnesoid X-activated receptor agonist cilofexor in participants with non-cirrhotic PSC. METHODS:In this phase 3, double-blind, placebo-controlled, multicentre trial (205 sites across 16 countries), adults aged 18-75 years with non-cirrhotic (F0-F3 [Ludwig classification]) large-duct PSC were randomly assigned (2:1) via an interactive web response system to receive cilofexor 100 mg or placebo (identical in appearance) orally once daily for 96 weeks. Randomisation was stratified by ursodeoxycholic acid use (yes or no) and the presence of bridging fibrosis (F3 vs F0-F2), with a block size of six within each stratum. Participants, personnel directly involved in the conduct of the study, and outcome assessors were masked to treatment assignment. The primary endpoint was the proportion of participants with histological progression of liver fibrosis (a stage increase of one or more [Ludwig classification]) at week 96. After study termination, the primary endpoint analysis set was amended to include all participants in the harms analysis set (all who received at least one dose of the study drug) who had biopsy data at baseline and week 96. This trial is complete (ClincalTrials.gov, NCT03890120). FINDINGS:Between June 13, 2019, and July 22, 2021, 419 participants were randomly assigned, and 416 were included in the full and harms analysis sets (cilofexor: n=277; placebo: n=139); 257 (62%) men and 159 (38%) women. The study was terminated early on Sept 26, 2022, after a planned interim futility analysis after 160 patients had reached 96 weeks of follow-up indicated a 6·8% probability of detecting a significant difference between cilofexor over placebo (futility boundary ≤10%). In the final analysis of the primary endpoint, for which 133 patients in the cilofexor group and 64 in the placebo group had liver biopsy results available, fibrosis progression occurred in 41 (31%) participants in the cilofexor group and 21 (33%) in the placebo group at week 96 (treatment difference -1·4% [95% CI -15·2 to 12·3]; p=0·42). The most common adverse events were pruritus (cilofexor: 136 [49%] of 277 patients; placebo: 50 [36%] of 139 patients; grade 3 or higher in 11 [4%] patients in the cilofexor group and one [1%] patient in the placebo group), COVID-19 (cilofexor: 65 [23%]; placebo: 26 [19%]), and upper abdominal pain (cilofexor: 40 [14%]; placebo 20 [14%]). The proportion of serious adverse events was similar between groups (cilofexor: 53 [19%]; placebo: 26 [19%]). There were no treatment-related deaths. INTERPRETATION:Cilofexor did not significantly reduce the rate of fibrosis progression (vs placebo) in participants with non-cirrhotic PSC. A greater percentage of cilofexor-treated participants had pruritus than placebo-treated participants; this study provides valuable harms data for cilofexor and other drugs in its class. FUNDING:Gilead Sciences.
BACKGROUND:Cholestatic pruritus is common and undertreated in primary biliary cholangitis (PBC) and negatively affects patients' lives. We aimed to evaluate the safety and efficacy of linerixibat, an ileal bile acid transporter inhibitor, as a specific antipruritic therapy in patients with PBC. METHODS:We conducted a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Patients with PBC and moderate-to-severe pruritus (Worst Itch Numerical Rating Scale [WI-NRS] ≥4) were recruited at 115 centres in 19 countries. Patients were randomly assigned to receive either oral linerixibat 40 mg twice a day or a matching placebo through an interactive online response system, with pruritus severity (moderate or severe) and concomitant pruritus treatment (bile acid binding resins, other treatments, or none) as stratification factors. The primary endpoint was change in pruritus over 24 weeks assessed using the WI-NRS, ranging from 0 (no itching) to 10 (worst imaginable itching). Efficacy analyses included all randomly allocated patients; safety analyses included all randomly allocated patients who received one dose of study treatment or more. This study is registered with ClinicalTrials.gov, number NCT04950127. FINDINGS:From Dec 1, 2021, to May 13, 2024, a total of 238 patients were randomly assigned to receive either linerixibat (n=119) or placebo (n=119). One (<1%) of 119 patients randomly allocated to receive placebo withdrew before receiving treatment. Patients receiving linerixibat experienced significant improvement in pruritus over 24 weeks compared with placebo (least-squares mean change from baseline -2·86 [95% CI -3·23 to -2·50] for linerixibat vs -2·15 [-2·51 to -1·78] for placebo; adjusted mean difference -0·72 [95% CI -1·15 to -0·28]; p=0·0013). Gastrointestinal adverse events were more frequent in patients treated with linerixibat than with placebo (72 [61%] of 119 vs 21 [18%] of 118 had diarrhoea; 22 [18%] vs four [3%] had abdominal pain). Treatment discontinuations due to gastrointestinal adverse events occurred in eight (7%) of 119 patients in the linerixibat group (of which five were due to diarrhoea) and one (<1%) of 118 in the placebo group. Serious adverse events were reported in 14 (12%) of 119 patients receiving linerixibat and four (3%) of 118 receiving placebo. No deaths were reported during the study. INTERPRETATION:Linerixibat significantly improved pruritus versus placebo, supporting its potential to address a major symptom of PBC. An expected increase in diarrhoea in linerixibat-treated patients was observed. FUNDING:GSK.
Metabolic-dysfunction-associated steatohepatitis (MASH) is the leading cause of chronic liver disease, but an incomplete understanding of MASH-induced liver fibrosis has limited therapeutic options. Here we show that hepatocyte caspase-8 drives MASH fibrosis through an apoptosis-independent mechanism. Hepatic caspase-8 expression correlates with liver fibrosis in both human and experimental MASH, and hepatocyte-specific caspase-8 deletion in male mice with MASH suppressed liver fibrosis and hepatic stellate cell (HSC) activation without affecting hepatocyte apoptosis. Mechanistic studies showed that a caspase-8–YY1 pathway in hepatocytes induces secretory meteorin (Metrn), which activates HSCs via a c-Kit–STAT3 pathway. Meteorin expression was increased in human and male mouse MASH livers and decreased by deletion of hepatocyte caspase-8 in MASH mice and human and mouse primary hepatocytes. Genetic restoration of hepatocyte meteorin in hepatocyte-caspase-8-deleted MASH mice restored HSC activation and liver fibrosis while silencing hepatocyte meteorin lowered liver fibrosis. These findings reveal a therapeutically targetable pathway promoting MASH fibrosis involving a non-apoptotic function of caspase-8 and a newly discovered HSC activator, meteorin. Hepatocyte caspase-8 in MASH promotes the activation of hepatic stellate cells and liver fibrosis through an apoptosis-independent mechanism
BACKGROUND:Cardiovascular-kidney-metabolic (CKM) syndrome, a new framework integrating cardiovascular, renal, and metabolic dysfunction, remains inadequately characterized in metabolic dysfunction-associated steatotic liver disease (MASLD). OBJECTIVE:We investigated the relationships between CKM stages and liver fibrosis severity, progression, and the risk of liver-related events (LREs) in MASLD. DESIGN:Patients with MASLD from the VCTE-Prognosis cohort were stratified according to CKM stages. Outcomes included the prevalence of advanced liver fibrosis (LSM ≥10 kPa), liver stiffness progression (≥20% increase and Baveno category upshift), and incident LREs. Associations were assessed using multivariable logistic regression and Cox proportional hazards models. RESULTS:Among 12,097 patients with MASLD, the prevalence of advanced liver fibrosis increased across CKM stages at baseline: 9.6% (CKM stage 0-1), 18.0% (CKM stage 2), and 31.6% (CKM stage 3-4). CKM stage 2 (adjusted OR=1.663, 95% CI 1.444-1.915) and CKM stage 3-4 (adjusted OR=2.575, 95% CI 2.109-3.144) were independently associated with advanced fibrosis. During a 4.5-year median follow-up, 716 patients (6.1%) experienced progression of liver stiffness, and 352 patients (1.7%) developed LRE. Compared with CKM stage 0-1, the risk of liver stiffness progression was higher in CKM stage 2 (adjusted HR=1.321, 95% CI 1.050-1.662; p =0.018) and CKM stage 3-4 (adjusted HR=1.767, 95% CI 1.339-2.330; p <0.001). In contrast, only CKM stage 3-4 were significantly associated with an increased risk of LREs (adjusted HR=1.975, 95% CI 1.245-3.133; p =0.004). CONCLUSIONS:CKM stages are independently associated with the severity and progression of liver fibrosis in MASLD. CKM stage 2 significantly increases liver stiffness progression without excess LRE risk, while CKM stage 3-4 confer the highest risk for liver-related outcomes.
Acute-on-chronic liver failure(ACLF)is one of the leading causes of mortality among patients with chronic liver disease.Potentially reversible,ACLF requires precise clinical classification to facilitate accurate diagnosis,targeted treatment,and comprehensive management.Based on the latest research findings and clinical evidence,the Severe Liver Disease and Artificial Liver Group and the Nutrition and Regeneration in End-Stage Liver Disease Group,Chinese Society of Hepatology,Chinese Medical Association,together with multidisciplinary experts,have jointly compiled China's first guideline for the diagnosis and treatment of ACLF.The guideline aims to provide guidance for the diagnosis,treatment,and individualized management of patients with ACLF in clinical practice.
BACKGROUND AND AIMS:Hepatic steatosis is characterised by hepatic lipid accumulation, inflammation and fibrosis, with macrophage polarisation playing a central role in disease progression. This study investigates the role of interleukin-25 (IL-25) in modulating macrophage polarisation and Notch signalling in a methionine-choline-deficient (MCD) diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) model. METHODS:C57BL/6 mice were fed a MCD diet to induce MAFLD. Human hepatocytes and primary hepatic macrophages were treated with palmitic acid and/or IL-25. Methods included RT-qPCR, ELISA, Western blot and immunofluorescence for gene/protein expression. ChIP and luciferase assays were used to analyse STAT3/Notch-1 signalling. RESULTS:We found that IL-25 expression was significantly downregulated in the livers of MCD-fed mice and in palmitic acid-treated hepatocytes. IL-25 treatment promoted M2 macrophage polarisation, evidenced by increased expression of Arg1, Chi3l3 and anti-inflammatory cytokines (IL-10, TGF-β), while suppressing pro-inflammatory cytokines (TNF-α, IL-6). Mechanistically, IL-25 inhibited the STAT3/Notch-1 pathway and induced IL-33, which negatively regulated the NF-κB/Jagged-1 axis, preventing M1 macrophage polarisation. Adoptive transfer of IL-25-induced M2a macrophages ameliorated hepatic steatosis and reduced ductular reaction in MCD-fed mice. CONCLUSIONS:These findings suggest a role for IL-25 in modulating macrophage polarisation and inflammation in metabolic dysfunction-associated fatty liver disease, supporting its further exploration as a potential therapeutic strategy for inflammatory liver diseases.
Introduction Neutrophils are initial responders in inflammation and contribute to non-alcoholic fatty liver disease (NAFLD) progression to steatohepatitis (NASH).Neutrophil extracellular traps (NETs) are implicated in liver injury, yet their precise mechanisms in NASH progression remains unclear. Objectives This study investigates how NETs drive NASH progression by exacerbating hepatocyte lipotoxicity and explore the regulatory mechanism of NETs formation and its downstream effects on liver pathology. Methods Clinical samples from NASH patients and diet-induced NASH mice were analyzed for NET levels. NETs were pharmacologically inhibited, and senescent cells were selectively eliminated in mice. Myeloid-specific RBP-J knockout mice were generated to disrupt Notch signaling, with subsequent evaluation of NET formation, senescence markers, steatosis, fibrosis, and inflammation. Results NETs were elevated in NASH patients and mice, correlating with hepatocyte senescence and lipotoxicity. Pharmacological NET disruption reduced hepatocyte senescence, accompanied by attenuated steatosis and fibrosis. Senescent cell clearance replicated these improvements, confirming liver senescence emerges is a vital step for NETs to promote the progression of NASH. Myeloid-specific Notch signaling ablation suppressed NET generation, concurrently decreasing lipid deposition and liver inflammation. Conclusion Our findings elucidate a novel mechanism by which neutrophil-derived Notch driven NETs exacerbate NASH by promoting cell senescence, thereby contributing to hepatic steatosis and fibrosis. This insight may provide potential intervention strategies and therapeutic targets for NASH treatment.
BACKGROUND AND AIMS:Reliable novel noninvasive biomarkers for the diagnosis of advanced liver fibrosis are urgently needed in clinical practice. We aimed to investigate the accuracy of plasma Follistatin-like protein 1 (FSTL-1) in the diagnosis of advanced liver fibrosis in chronic liver diseases. APPROACH AND RESULTS:We collected cross-sectional clinical data for a derivation cohort (n = 86) and a validation cohort (n = 431), totaling 517 subjects with liver biopsy. Advanced liver fibrosis was defined by the METAVIR pathological score (F ≥3). Dual cutoff values for diagnosis were explored. In the derivation cohort, plasma FSTL-1 levels were significantly elevated in patients with advanced liver fibrosis, with an AUROC of 0.85 (95% CI, 0.75-0.96). In the validation cohort, plasma FSTL-1 maintained good diagnostic performance, with an AUROC of 0.88 (95% CI, 0.83-0.92). Plasma FSTL-1 levels were significantly associated with individual histological features of the METAVIR scoring system, including interface hepatitis, lobular necrosis, and hepatocellular ballooning (p < 0.0001). A cutoff value ≤ 0.43 ng/mL was the optimal rule-out threshold, with a sensitivity of 84.62% (95% CI, 76.46%-90.30%) and a specificity of 79.51% (95% CI, 74.81%-83.53%), while ≥0.50 ng/mL was the best rule-in threshold, with a specificity of 86.41% (95% CI, 81.06%-90.43%) and a sensitivity of 70.67% (95% CI, 64.41%-76.23%). CONCLUSIONS:Plasma FSTL-1 has high diagnostic accuracy and could potentially reduce the need for liver biopsy in identifying patients with advanced liver fibrosis.
Background Xalnesiran, a small interfering RNA molecule that targets a conserved region of the hepatitis B virus (HBV) genome and silences multiple HBV transcripts, may have efficacy, with or without an immunomodulator, in patients with chronic HBV infection. Methods We conducted a phase 2, multicenter, randomized, controlled, adaptive, open-label platform trial that included the evaluation of 48 weeks of treatment with xalnesiran at a dose of 100 mg (group 1), xalnesiran at a dose of 200 mg (group 2), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod (group 3), xalnesiran at a dose of 200 mg plus 180 mu g of pegylated interferon alfa-2a (group 4), or a nucleoside or nucleotide analogue (NA) alone (group 5) in participants with chronic HBV infection who had virologic suppression with NA therapy. The primary efficacy end point was hepatitis B surface antigen (HBsAg) loss (HBsAg level, <0.05 IU per milliliter) at 24 weeks after the end of treatment. Safety was also assessed. Download a PDF of the Plain Language Summary. Results Among 159 participants (30, 30, 34, 30, and 35 in groups 1 through 5, respectively), the primary end-point event occurred in 7% (95% confidence interval [CI], 1 to 22) of those in group 1, in 3% (95% CI, 0 to 17) of those in group 2, in 12% (95% CI, 3 to 28) of those in group 3, in 23% (95% CI, 10 to 42) of those in group 4, and in none (95% CI, 0 to 10) of those in group 5. In groups 1 through 5, respectively, HBsAg seroconversion occurred in 3%, none, 3%, 20%, and none of the participants at 24 weeks after the end of treatment. HBsAg loss with or without seroconversion occurred only in participants with a screening HBsAg level below 1000 IU per milliliter. In groups 1 through 5, respectively, grade 3 or 4 adverse events occurred in 17%, 10%, 18%, 50%, and 6% of the participants, with the most frequent event being an elevated alanine aminotransferase level. Conclusions Among participants with chronic HBV infection who had virologic suppression with NA therapy, treatment with xalnesiran plus an immunomodulator resulted in HBsAg loss at 24 weeks after the end of treatment in a substantial percentage of participants. Grade 3 or 4 adverse events were not uncommon.
BACKGROUND & AIMS:Intrahepatic cholestasis of pregnancy (ICP) is the most common and high-risk liver disorder during pregnancy, with varying prevalence across populations. Our understanding of the mechanisms underlying ICP and population-level differences remains limited. This study delves into the genetic etiology of ICP in East Asians, drawing comparisons with Europeans to comprehend ICP etiology in the context of genetic background and evolution. METHODS:We conducted the hitherto largest-scale genome-wide association study on fasting total serum bile acids (TBA) and ICP in 98,269 Chinese pregnancies. The findings were replicated in three cohorts and compared with European populations. Additionally, phenome-wide association and spatio-temporal evolution analyses were employed to investigate the function and evolutionary patterns of ICP-associated loci. RESULTS:We identified eight loci for fasting TBA and four for ICP, including ten novel loci. Notably, we discovered an East Asian-specific locus within a 0.4 Mbp region at 14q24.1, which increases fasting TBA by 6.12 μmol/L and ICP risk by 16.56-fold per risk allele (95% CI 16.43 to 16.69, p = 7.06×10-381). Phenome-wide association and spatial-temporal evolution analyses revealed that this 14q24.1 ICP risk locus confers resistance to hepatitis B and has become prevalent in East and Southeast Asia within the last 3,000 years. CONCLUSIONS:We uncovered a distinct genetic etiology of ICP in East Asians, likely linked to a historic HBV epidemic in East and Southeast Asia within the last 3,000 years. These findings enhance our understanding of ICP pathophysiology and offer potential for more precise detection, assessment, and treatment of the disorder. IMPACT AND IMPLICATIONS:This study provides novel insights into the genetic basis of intrahepatic cholestasis of pregnancy (ICP) in East Asian populations, where little was previously known. The identification of the East-Asian-specific 14q24.1 locus, associated with both fasting total serum bile acids and ICP, and its connection to a historical hepatitis B epidemic emphasize the importance of incorporating population-specific history into disease research. These findings are crucial for researchers studying pregnancy-related liver disorders and clinicians providing care to pregnant women, enabling more accurate screening, risk assessment, and targeted interventions for ICP.
