Matrix stiffness increases during fibrosis and drives hepatic stellate cell (HSC) activation through YAP-dependent mechanotransduction. Although recent studies have revealed HSC heterogeneity beyond classical quiescent and fully activated states, how physiological-range stiffness influences activation trajectories underlying this heterogeneity remains unclear. This study aimed to determine how substrate stiffness shapes the transcriptomic profiles and biases activation trajectories. We performed time-resolved single-cell RNA sequencing of primary mouse HSCs cultured on stiffness-tunable polydimethylsiloxane (PDMS) substrates (Soft, 0.2 kPa; Hard, 32 kPa), using tissue culture polystyrene (TCPS) as a conventional baseline. In vitro findings were anchored to public in vivo datasets from mouse and human liver injury. Matrix stiffness altered HSC morphology and transcriptional state, with softer substrates promoting a rounder phenotype and reducing the expression of activation markers, particularly during early activation. Pseudotime and RNA velocity analyses also revealed different early trajectories associated with matrix stiffness. Under the soft condition, HSCs exhibited an expanded quiescent-to-initiatory transitional state characterized by Nrf2-related features and regeneration-associated factors, including Hgf and Rspo3. In contrast, the hard condition induced a gene signature, which was upregulated from early stages of HSC activation onward, localized to fibrotic septa in human liver and correlated with cirrhosis severity in an HCV patient cohort. Matrix stiffness shapes early HSC activation trajectories toward transcriptional programs associated with regeneration or fibrosis. These findings support stiffness-controlled culture systems as improved models of HSC activation and provide a framework for regenerative and antifibrotic strategies.
Hepatocellular carcinoma (HCC) is a rapidly increasing healthcare burden in Australia. We aimed to evaluate the contemporary epidemiology, clinical characteristics, and real-world patterns of care for HCC in Australia using a prospective multicentre clinical quality registry. This interim analysis utilised data from the Upper Gastrointestinal Cancer Registry (UGICR) HCC module, a multicentre clinical quality registry involving 17 major centres across all mainland Australian states. Patients with a new diagnosis of HCC from 1 January 2021 were included. Clinical characteristics and initial treatment modalities were compared between liver transplant centres (LTCs) and non-transplant centres (NTCs). A total of 489 patients were analysed (333 LTC, 156 NTC). The cohort was predominantly male (76.7
Glucagon-like peptide-1 receptor agonists (GLP-1 RA) may influence pathways involved in hepatocarcinogenesis, but evidence regarding their association with hepatocellular carcinoma (HCC) and mortality risk remains heterogeneous. We evaluated the association between GLP-1 RA initiation and HCC incidence compared with commonly used glucose-lowering medications, with secondary exploratory analyses of all-cause mortality following HCC diagnosis. We emulated active-comparator, new-user target trials using Patient-Centered Clinical Research Network data from UT Southwestern Medical Center (PCORnet–UTSW; 2010–2025). Adults with T2D initiating GLP-1 RA were compared with initiators of metformin, insulin, sodium–glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), and sulfonylureas. The primary outcome was incident HCC; a secondary analysis evaluated all-cause mortality after HCC diagnosis. Five-year risks and risk differences under the intention-to-treat (ITT) approach were estimated using pooled logistic regression with inverse probability of treatment weighting. Per-protocol analyses accounted for treatment adherence using inverse probability of censoring weights. GLP-1 RA initiators had lower five-year HCC risk than comparator groups. Under ITT, risk differences were − 0.37
Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic metabolic disorder associated with extrahepatic organ damage, including chronic kidney disease (CKD). The Fibrosis-4 (FIB-4) index is a validated non-invasive tool for estimating hepatic fibrosis severity. This study aimed to investigate whether FIB-4-defined hepatic fibrosis is independently associated with reduced estimated glomerular filtration rate (eGFR) in a large, real-world Turkish MASLD cohort. This is a cross-sectional analysis of the prospective, nationwide, multicenter DAHUDER MASLD Study, which enrolled patients from 44 internal medicine outpatient clinics across 31 provinces representing all 12 statistical regions of Türkiye. A total of 10,873 MASLD patients were included. MASLD was defined as ultrasonographic hepatic steatosis in the presence of at least one cardiometabolic risk factor. High FIB-4 was defined as ≥ 1.3 for patients aged < 65 years and ≥ 2.0 for those aged ≥ 65 years, per EASL–EASD–EASO 2024 guidelines. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Age-stratified multivariate linear regression models were constructed to identify independent predictors of eGFR. High FIB-4 was detected in 11.2
The prognostic value of on-treatment hepatitis B virus (HBV) RNA, hepatitis B core-related antigen (HBcrAg), and quantitative hepatitis B surface antigen (HBsAg) for hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B (CHB) remains uncertain. We evaluate the predictive roles of these viral markers in patients with CHB receiving long-term entecavir therapy. This prospective, multicenter study enrolled patients with CHB-related cirrhosis undergoing long-term entecavir treatment and HCC surveillance in Taiwan. Serum HBV RNA, HBcrAg, and HBsAg levels were measured at enrollment. Multivariable regression identified predictors of HBV RNA positivity and HCC development. Overall, 451 patients were included. After a median of 6.2 years of antiviral therapy, the median levels of HBV RNA, HBcrAg, and HBsAg were 0.9 log10 copies/mL, 3.2 log10 U/mL, and 2.4 log10 IU/mL, respectively. During a median 3.3-year follow-up, 55 developed HCC. 57.2
Bepirovirsen, an antisense oligonucleotide that targets all hepatitis B virus (HBV) mRNAs, is in development for the treatment of chronic HBV infection. Clinical studies have demonstrated that bepirovirsen has multiple mechanisms of action, including lowering HBV DNA, reducing viral protein production, and inducing immune activation. Post hoc analysis of biomarker samples from three studies was performed to further characterize changes in soluble protein biomarkers after bepirovirsen dosing. Across three studies (CS3 [NCT02981602] in participants with chronic HBV infection; PFS [NCT06058390] and QTc [NCT06422767] in healthy volunteers) participants received bepirovirsen (150 mg, 300 mg, or 450 mg) or placebo. Longitudinal serum samples were taken for exploratory proteomics analysis. Relative expression of soluble proteins, including immune-related biomarkers, was measured, and differential expression was determined across arms. Clustering analysis was performed to identify kinetic patterns. Bepirovirsen induced significant, transient protein differential expression in the hours after dosing, while there were relatively minor changes in placebo. There were many similarities in protein biomarkers induced in CS3 participants with chronic HBV infection and in the two healthy volunteer studies. Additionally, bepirovirsen treatment increased abundance of many proteins to a higher degree with increasing dose. These findings strengthen the association between bepirovirsen treatment and changes in innate immune-related proteins and indicate that this effect does not require the presence of HBV. The kinetic patterns of protein expression suggest that there are multiple waves of protein induction, which could impact recruitment and activation of innate and adaptive immune cell types. NCT02981602, NCT06058390, NCT06422767. Bepirovirsen induces proteomic changes consistent with a transient innate immune response in healthy volunteers and participants with chronic HBV infection
Despite sustained universal infant hepatitis B vaccination, chronic hepatitis B (CHB) remains an important cause of cirrhosis and hepatocellular carcinoma in Thailand, particularly among adults born before vaccine implementation. This article summarizes the 2026 National Guideline on Elimination of Viral Hepatitis B in Thailand and presents a health-system framework for addressing the remaining disease burden. The guideline was developed by a multidisciplinary expert panel using evidence from international recommendations, peer-reviewed literature, national epidemiological data, implementation studies, and health economic analyses. The recommendations were formulated using the GRADE framework and adapted for implementation within Thailand’s Universal Health Coverage system. The national strategy prioritizes birth-cohort HBsAg screening for adults born before 1992, simplified evidence-based treatment eligibility incorporating non-invasive fibrosis assessment and virological criteria, and first-line use of high genetic-barrier nucleos(t)ide analogs. Prevention of mother-to-child transmission prioritizes HBV DNA-guided antiviral prophylaxis, with simplified implementation pathways reserved for settings with substantial diagnostic constraints. Long-term care emphasizes structured monitoring, appropriate specialist referral, conservative treatment discontinuation criteria, defined retreatment thresholds, and risk-based semiannual ultrasound surveillance for hepatocellular carcinoma. Integration with antenatal services, HIV programs, and primary care facilities supports decentralized delivery and continuity of care. Thailand’s 2026 hepatitis B guideline operationalizes evidence-based CHB management within a publicly financed decentralized health system and provides a scalable model for expanding hepatitis B diagnosis and treatment in endemic settings.
Gout frequently co-occurs with steatotic liver disease, but its direct hepatotoxic effect beyond obesity remains contentious. We aimed to elucidate the independent association between gout and hepatic fibro-inflammation, particularly in subclinical cases with normal alanine aminotransferase (ALT). This multi-cohort study integrated a UK Biobank discovery cohort (N = 21,334) using MRI iron-corrected T1 (cT1) mapping, and a multicenter clinical validation cohort (N = 512) using Transient Elastography (FibroScan) to measure liver stiffness (LSM). Multivariable regression and causal mediation analyses dissected “obesity-dependent” versus “independent” pathways. Gout patients exhibited significantly elevated liver fibro-inflammation and steatosis across both cohorts. After full adjustment for metabolic confounders, gout was independently associated with liver injury in the UK Biobank (β-cT1 = 6.41 ms, p = 0.025) and clinical cohort (β-LSM = 1.21 kPa, p < 0.001). This association consistently persisted in non-obese patients with normal ALT (< 40 U/L), indicating occult injury. Mediation analysis revealed a “Double Hit” mechanism: 51.3
The underlying mechanisms of the associations between dietary patterns and liver disease remain unclear. We aimed to identify metabolic signatures (MSs) reflecting adherence to ten healthy dietary patterns and to investigate their associations with metabolic dysfunction-associated steatotic liver disease (MASLD) and cirrhosis. This cohort study included 82,259 participants with detailed dietary and metabolomic data. MSs for each dietary pattern were derived using elastic-net regression. Cox proportional hazards regression, Mendelian randomization, and mediation analyses were employed to explore potential associations and mechanisms. MSs for ten healthy dietary patterns were derived from 31 to 116 metabolites, primarily comprising fatty acids, lipids, and lipoprotein subclasses. Across all patterns, MSs were consistently associated with a lower risk of MASLD, with hazard ratios (HRs) ranging from 0.59 to 0.76. Notably, MSs for MIND, HPDI, rE-DII, and HLCD were associated with reduced cirrhosis risk (HRs: 0.56 to 0.63). Mendelian randomization analysis supported a potential causal relationship between MSs of MED, MIND, HPDI, and EAT-Lancet diets and liver diseases. Mediation analysis revealed that specific MSs accounted for 20.1
The Asian Working Group for Sarcopenia (AWGS) updated its criteria in 2025, adding a body mass index (BMI)-adjusted muscle index (ASM/BMI) to the conventional skeletal muscle index (SMI). We aimed to compare the prognostic performances of the AWGS 2019 and AWGS 2025 in patients with liver cirrhosis. This retrospective cohort study included 505 patients ≥ 50 years of age with liver cirrhosis who underwent bioelectrical impedance analysis between 2016 and 2025. Sarcopenia was defined using the AWGS 2019 SMI, AWGS 2025 SMI, and AWGS 2025 ASM/BMI criteria. Landmark analysis was performed on day 180, and overall survival was evaluated. The prognostic performance was assessed using Cox regression, time-dependent ROC analysis, and Harrell’s C-index. During a median follow-up of 5.4 years, 140 deaths occurred. Sarcopenia, as defined by each definition, was independently associated with mortality. The baseline model (age, sex, etiology, and ALBI score) showed a C-index of 0.732. The addition of sarcopenia improved discrimination for SMI-based definitions (ΔC-index 0.033 for AWGS 2025 SMI; 0.023 for AWGS 2019 SMI) but not for AWGS 2025 ASM/BMI (ΔC-index 0.005). At 3 years, the AUC values were 0.828 (AWGS 2025 SMI), 0.822 (AWGS 2019 SMI), and 0.800 (AWGS 2025 ASM/BMI), relative to 0.792 for the baseline model. AWGS 2025 SMI demonstrated robust prognostic performance comparable to or slightly better than that of the AWGS 2019, whereas the AWGS 2025 ASM/BMI provided limited incremental prognostic value. The height-adjusted SMI remains a reliable metric for risk stratification in cirrhosis.
Metabolic dysfunction-associated steatotic liver disease (MASLD) was the most rapidly growing liver disease worldwide. We aimed to investigate the temporal trends in prevalence and risks of MASLD in Taiwan, 2001–2021. We enrolled participants from two large cohorts. Steatotic liver disease (SLD) was defined by either abdominal ultrasound, or serum panels. MASLD was defined as SLD with at least one cardiometabolic risk factor (CMRF). The endpoints were the changes in prevalence and risks of SLD, MASLD and CMRF. A total of 426,478 participants (mean age, 42.0 ± 13.3 years; 57.2
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent condition with significant cardiometabolic and hepatic risks. Tirzepatide, a dual GLP-1/GIP receptor agonist, shows promise in MASLD, but real-world comparative data against sodium-glucose cotransporter-2 inhibitors (SGLT2is) are lacking. In this multicenter, retrospective, propensity score-matched cohort study using the TriNetX US Collaborative Network, we compared outcomes in 43,743 new tirzepatide initiators versus 43,743 matched SGLT2i users with MASLD and ≥ 1 metabolic comorbidity. Propensity Score Matching (1:1, caliper 0.1) balanced > 50 covariates. Primary outcomes included all-cause mortality, hospitalization, major adverse cardiovascular events (MACE), major adverse liver outcomes (MALO), and major adverse kidney events (MAKE) at 1- and 3-year follow-up, analyzed via Kaplan–Meier estimation and Cox proportional hazards models. Tirzepatide was associated with significantly lower risks versus SGLT2is. At 1-year follow-up (n = 43,743 per group), all-cause mortality events were 144 (cumulative incidence 0.48
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder linked to metabolic syndrome, but its extrahepatic drivers and persistence mechanisms remain unclear. Transcriptomics was performed on adipose-derived stem cells (ADSCs) from distinct adipose depots in dynamic MASLD mouse models. A dietary reversal model was used to assess transcriptional retention. Candidate genes were identified via integrated DNA methylome and transcriptome analysis. Cyp26b1 function was tested by perirenal ADSCs-specific knockdown, and involved downstream mechanisms were investigated. Perirenal ADSCs exhibited an early dysregulated transcriptional signature in MASLD and retained high transcriptional retention after reversal. Multi-omics identified Cyp26b1 as a persistent, epigenetically regulated driver. Knockdown of Cyp26b1 in perirenal ADSCs attenuated MASLD progression, potentially by modulating the CCL3–CCR5 axis to alleviate hepatic steatosis and inflammation. This study reveals an ADSC-mediated perirenal adipose–liver axis and establishes pathological "memory" in ADSCs as a perpetuating factor in MASLD. Transcriptional retention in perirenal ADSCs and its key regulator Cyp26b1 represent potential theoretical targets for exploring the mechanism and intervention of cellular "memory" in MASLD.
Globally, especially in the Asia Pacific region, chronic hepatitis B infection has led to an undesirable escalating morbidity and mortality with acute-on chronic liver failure, end-staged liver cirrhosis, and hepatocellular carcinoma. This has happened despite the past four decades of major scientific advances made in screening methods, vaccination strategies, highly effective low-cost anti-viral therapies, and surveillance strategies for early detection of hepatocellular carcinoma. To address this health threat, APASL has formed a Viral Elimination Taskforce to unite key opinion leaders from its member countries and regions. The ongoing shifts in hepatitis B epidemiology, socioeconomic changes, and advancements in technology are taken into consideration. With the conjoint efforts of all the members of the APASL Viral Elimination Taskforce, these clinical practice guidelines have been formulated aiming to facilitate healthcare professionals, policy-makers, and patients in making practical and cost-effective management decisions for chronic hepatitis B infection. Altogether, it provides recommendations in 13 major areas related to screening, vaccination, treatment, and HCC surveillance. The implementation of these clinical practice guidelines represents major APASL effort toward elimination of the disease burden due to chronic hepatitis B infection in Asia Pacific region.
This study aimed to investigate the efficacy of radiation therapy and targeted therapy combined with or without immunotherapy for hepatocellular carcinoma (HCC) patients with lymph node metastases (LNM). A total of 132 HCC patients with LNM were enrolled in this study. Propensity score matching (PSM) and stabilized inverse probability of treatment weighting (sIPTW) were used to balance baseline variables between groups. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and clinical safety were compared between the two treatment arms. There were 61 patients in radiotherapy plus targeted therapy (RT) group, and 71 patients in radiation therapy, targeted therapy combined with immunotherapy (RTI) group. In the overall cohort, the median OS was 12.8 months in the RT group and 18.8 months in the RTI group (p = 0.003). Multivariate analysis identified that tumor thrombus status, distant metastasis, lymph node (LN) number, LN size and immunotherapy were independent prognostic factors for survival. Median PFS was 7.0 months in the RT group and 11.9 months in the RTI group (p = 0.001). The ORRs were 70.5
