Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease in which many patients respond inadequately to ursodeoxycholic acid (UDCA) and may progress to liver failure. Although research on PBC has primarily centered on lymphocyte-mediated mechanisms, increasing evidence implicates neutrophils in autoimmunity, yet their role in PBC remains unclear. Cytokine screening of patient sera collected from our medical center was performed to identify NETs-inducing factors. Transcriptomic profiling was conducted to determine the molecular effects of NETs on cholangiocytes. The therapeutic effects of the neutrophil elastase inhibitor sivelestat on NETs-associated injury were evaluated in dnTGFβRII and 2OA–BSA murine models of PBC. We identify NETs as a critical mediator linking immune activation to biliary injury. NETs formation was markedly elevated in PBC patient samples and murine models. Exploratory cytokine profiling of patient serum samples prioritized resistin as a leading candidate mediator of NETs formation, and elevated circulating resistin levels were confirmed in an independent clinical cohort. Further analysis of patient clinical data revealed that circulating resistin levels were positively correlated with cholestasis. Transcriptomic profiling demonstrated that NETs exposure downregulated ZNF709 and activated the TP53–MDM2 pathway in cholangiocytes, leading to epithelial injury and PBC-like phenotypic changes. In vivo, treatment with sivelestat significantly reduced biliary inflammation and fibrosis, while combination therapy with UDCA produced synergistically therapeutic benefits. These findings identify a resistin–NETs–ZNF709 axis that links neutrophil activation to cholangiocyte injury in PBC and suggest that targeting NETs-associated injury with sivelestat may represent a potential strategy to improve current PBC therapies.
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.
