The Chinese Society of Hepatology of the Chinese Medical Association has invited experts in relevant fields to revise and rename the 2019 "Chinese Guidelines on the Management of Liver Cirrhosis" to "Chinese Guidelines for Clinical Diagnosis, Treatment, and Management of Cirrhosis (2025)". These updated guidelines are aimed at providing recommendations for the clinical diagnosis and management of liver cirrhosis across the compensated, decompensated, and recompensated stages, as well as guidance on cirrhosis reversal and associated complications.

Chronic liver diseases of diverse etiologies, along with primary liver cancers, represent major global health burdens with limited curative options. CD8+ T-cell exhaustion is a central barrier to effective immune control in these pathological settings. However, precursor exhausted CD8+ T cells (Tpex), a stem-like subset with self-renewal and proliferative potential, retain the ability to generate effector-like progeny and sustain long-term immune surveillance. In this review, we first provide a definition of Tpex to distinguish them from other related CD8+ T-cell states, including terminally exhausted, effector-like exhausted, tissue-resident memory, and conventional memory T cells, in chronic liver diseases and liver cancer. We then summarize current knowledge on the fundamental biology, etiological dynamics, and therapeutic relevance of Tpex in both benign and malignant liver diseases. Specifically, we examine the transcriptional, metabolic, and microenvironmental networks that govern Tpex fate, with particular emphasis on how distinct etiologies, including viral hepatitis, metabolic dysfunction-associated steatotic liver disease, and autoimmune hepatitis, differentially shape Tpex abundance and functional state. In chronic viral hepatitis, Tpex dynamics are critically influenced by viral persistence, metabolic context, and co-infections, which in turn have direct implications for the responsiveness to immune checkpoint blockade. In hepatocellular carcinoma and intrahepatic cholangiocarcinoma, Tpex signatures are not only correlated with clinical outcomes but also modulated by tumor genetic landscapes and the composition of the immune microenvironment. Finally, we highlight emerging Tpex-targeted therapeutic strategies, including co-stimulatory agonists, metabolic reprogramming, vaccines, CAR-T cell engineering, and gut microbiota modulation, as promising avenues to overcome immunotherapy resistance.

The potential for recompensation and its defining criteria in patients with decompensated cirrhosis due to primary biliary cholangitis (PBC) remain poorly defined. Therefore, our study aimed to explore the criteria for etiological suppression and provide preliminary insights into PBC recompensation. In this retrospective-prospective study, we enrolled hospitalized patients with PBC cirrhosis from January 2014 to June 2023. Recompensation was defined according to the Baveno VII criteria. In addition, expanded recompensation criteria were evaluated for patients on low-dose diuretics and/or lactulose/rifaximin with resolution of decompensation and stable improvement of liver function. We explored whether the biochemical responses to UDCA could serve as surrogates for etiological suppression. We enrolled 240 patients with PBC cirrhosis (122 compensated and 118 decompensated). With a median follow-up of 50.0 (31.0, 72.0) months, 18 (15.3

Fibrosis is a key predictor of the long-term prognosis in metabolic dysfunction-associated steatotic liver disease (MASLD). Numerous clinical trials in drug development for MASLD have used fibrosis improvement as an efficacy endpoint. We aim to compare the efficacy of pharmacologic therapies for MASLD in improving fibrosis using histopathological and noninvasive assessments. A comprehensive search for randomized controlled trials (RCTs) was conducted across multiple databases, focusing on drug therapy in adult patients with MASLD. The primary outcome was more than 1-stage fibrosis improvement. The secondary outcomes included changes in liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE) and magnetic resonance elastography. Each intervention's ranking probability was assessed using the surface under the cumulative ranking curve (SUCRA). Forty-eight RCTs involving 10 119 participants were included. For the primary outcome, pegozafermin, obeticholic acid (OCA), and resmetirom all outperformed placebo in the fibrosis stage F1-3 analysis. OCA was superior to placebo in the 1.5-year analysis. Pegbelfermin (SUCRA: 77.11%) and pegozafermin (SUCRA: 74.91%) at F1-3, and OCA at 1.5 years (SUCRA: 81.64%) were ranked as the most effective treatments. For the secondary outcome, pegozafermin significantly outperformed placebo for decreasing LSM via VCTE in 0.5-year analysis, ranking as the most effective treatment for this outcome (SUCRA: 96.98%). Several new drugs currently in clinical trials have shown potential therapeutic effects for fibrosis improvement in MASLD patients, especially those targeting fibroblast growth factor 21 (FGF21). More definitive efficacy will depend on the results of phase III clinical trials.

Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is a highly prevalent condition, yet its molecular mechanisms remain incompletely understood. We explored circulating protein signatures and their causal relationships with MAFLD using large-scale proteomic and genomic data from the UK Biobank. Baseline plasma levels of 2923 circulating proteins were quantified in 49,206 participants (744 MAFLD outcomes). Protein-MAFLD associations were evaluated using multivariable Cox regression, followed by cis-Mendelian randomization (cis-MR) to infer causal effects based on protein quantitative trait loci. Among 215 proteins associated with MAFLD risk, four proteins (FURIN, LILRB4, NFASC, and PRAP1) showed causal evidence by cis-MR. FURIN, a proprotein convertase that activates transforming growth factor-β (TGF-β), emerged as the strongest causal effector. Downstream TGF-β signaling molecules (TGFB1, TGFBR2, SMAD1, and SMAD5) were significantly elevated in MAFLD cases, supporting activation of the FURIN/TGF-β axis. Additionally, 30 TNF-α-related proteins, including TNF, TNFRSF1A, TNFRSF1B, JUN, FOS, MAPK9, and MAPK13, were significantly upregulated in MAFLD, suggesting upstream regulation of FURIN by inflammatory TNF-α signaling. Our integrative cohort and genetic analyses reveal FURIN as a causal mediator in MAFLD pathogenesis through activation of TGF-β signaling, potentially modulated by inflammatory TNF-α signaling. These findings highlight the TNF-α/FURIN/TGF-β cascade as a potential molecular target for early prediction and therapeutic intervention in MAFLD.

BACKGROUND AND AIM:The development of novel agents with curative intent for chronic hepatitis B (CHB) has accelerated, but few candidates transition to phase III trials. We evaluated trial design features associated with registry-defined trial completion and phase transition, and synthesized end-of-treatment hepatitis B surface antigen (HBsAg) decline as an on-treatment antiviral signal. METHODS:We systematically reviewed clinical trial registries and bibliographic databases for CHB cure trials. Associations between trial design characteristics and trial performance were analyzed using Cox regression (time to registry-defined completion), logistic regression (phase I to phase II transition), and random-effects meta-analysis of end-of-treatment HBsAg decline. RESULTS:Larger sample size (HR = 0.819, 95% CI = 0.710-0.945) and longer treatment duration (HR = 0.897, 95% CI = 0.816-0.987) were associated with a lower likelihood of registry-defined completion in phase I trials. In phase II trials, larger sample size was associated with a lower likelihood of registry-defined completion (HR = 0.936, 95% CI = 0.879-0.997). Novel trial designs were not associated with faster completion. Among phase I trials with a definitive status, trials enrolling healthy volunteers were more often followed by phase II registration (adjusted OR = 2.82, 95% CI = 1.16-7.08). Meta-analysis showed that direct-acting antivirals were associated with marked end-of-treatment HBsAg decline (SMD = 1.28, 95% CI = 0.47-2.08). CONCLUSIONS:Smaller and shorter early-phase trials were more likely to complete, whereas novel trial designs were not associated with faster completion. Direct-acting antivirals showed marked end-of-treatment HBsAg decline, an on-treatment signal rather than durable functional cure.

Atezolizumab plus bevacizumab (Atez/Bev) is the first-line treatment for unresectable hepatocellular carcinoma (HCC). This study investigated the association of adverse events (AEs) with clinical outcomes by treatment relation, organ systems, and severity. This exploratory post hoc analysis included 435 HCC patients treated with Atez/Bev, 136 patients with sorafenib, and 58 patients with atezolizumab monotherapy from the IMbrave150 (NCT03434379) and GO30140 (NCT02715531) trials. Kaplan-Meier analysis was applied to estimate overall survival (OS) in patients treated with Atez/Bev for ≥ 3 months. Landmark analysis at 3 months restricted the OS analysis to 332 patients who completed ≥ 3 months of Atez/Bev. Among these patients, treatment-related renal/urinary, mild vascular, and skin/subcutaneous AEs were associated with improved OS compared with patients without the corresponding AE (mOS: not reached vs. 20.2 months, p < 0.001; not reached vs. 20.2 months, p < 0.001; and not reached vs. 22.8 months, p = 0.014, respectively). Experiencing one (HR = 0.56, 95

We aimed to compare the association of metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), metabolic dysfunction and ALD (MetALD), and MASLD with viral hepatitis (MASLD-Viral) with risks of cirrhosis, liver cancer, and mortality. The data of 464,556 adults from the UK Biobank (UKB), 13,526 adults from the National Health and Nutrition Examination Survey (NHANES), and 2554 adults from BeijngFH Health Cohort Study (FHCS) were included. Adjusted hazard ratios (aHR) and odds ratios were calculated using Cox and Logistic regression models, respectively. Compared with non-SLD, the risk of liver cancer increased from MetALD (aHR 1.70 [95% CI 1.37, 2.09]), MASLD (1.91 [1.66, 2.21]), MAFLD (2.01 [1.76, 2.29]), ALD (3.16 [2.54, 3.93]), to MASLD-Viral (22.0 [10.8, 44.4]) in a stepwise manner in the UKB; the risk of all-cause mortality increased from MetALD, MASLD, MAFLD, ALD, to MASLD-Viral in the NHANES. The odds ratio of liver fibrosis increased from MASLD, MAFLD, to MASLD-Viral in the FHCS. In patients with diabetes, metformin plus other drugs were associated with higher risks of cirrhosis, liver cancer, and all-cause mortality in MASLD or MAFLD. Prevention rather than antiglycemic treatment is important for patients with diabetic MASLD or MAFLD.

Background/Aims : Noninvasive indexes can be used to diagnose and stage liver fibrosis caused by chronic hepatitis B (CHB). We aimed to evaluate whether changes in the liver stiffness measurement (LSM) and serum biomarkers can predict liver fibrosis regression in CHB patients based on triple liver biopsies. Methods : This multicenter cohort study was based on triple liver biopsies and lasted for 260 weeks. Liver fibrosis regression was defined as Ishak decreased ≥1 stage or predominantly regressive by P-I-R classification with stable Ishak stage. Twelve noninvasive models were validated externally and yielded area under the receiver operating characteristic curve (AUROC) values ≥0.700 for predicting significant fibrosis in the training set. Results : A total of 175 CHB patients were included (median age: 38 years, 76.6% male). A total of 69.2% (117/169) and 79.6% (78/98) patients achieved liver fibrosis regression at week 78 and week 260, respectively. The mixed effects model revealed significant group×time interactions between the regression and non-regression groups for aminotransferase to platelet ratio index (APRI; p=0.041), new algorithm attributed to age, alanine aminotransferase, gamma-glutamyl transferase algorithm (p=0.022), and King’s score (p=0.016) from baseline to week 78 as well as for APRI (p=0.046) from baseline to week 260. The AUROC values for model changes were all <0.750 for predicting liver fibrosis regression. Additionally, the changes in the LSM and most noninvasive models were significantly correlated with the changes of Ishak-histology activity index score. Conclusions : Changes in the LSM and noninvasive models were not strong predictors of liver fibrosis regression after 78 weeks and 260 weeks of treatment among CHB patients. It is critical to develop a dynamic noninvasive model for assessing liver fibrosis regression (ClinicalTrials.gov identifier NCT02849132).

OBJECTIVES:Patient prognosis for hepatocellular carcinoma (HCC) varies significantly even when they share the same clinical stage. We aimed to characterize the stage-specific transcriptomic landscape in super survivors with HCC and develop a prognostic gene signature for the prediction of patient survival. METHODS:Data from The Cancer Genome Atlas (TCGA) among 76 age- and sex-matched super (alive at 5 years) and poor survivors (deceased within 1 year) with HCC were analyzed. Gene set enrichment analysis stratified by tumor stage was conducted, and a key prognostic gene signature was developed. The gene signature was then validated by using the whole TCGA cohort and the independent International Cancer Genome Consortium (ICGC) cohort. RESULTS:Stage-specific transcriptomic profiling revealed that stages I and II HCC cases showed positive enrichment in immune response pathways, while stage III tumor exhibited enhanced catabolic activities but reduced glycolysis. Across all tumor stages, cell cycle biological processes were less active in super survivors. A 19-gene signature, incorporating immune-, metabolism-, and cell cycle-related genes, accurately distinguished super survivors from poor survivors with 90.8% accuracy. The gene signature reliably predicted overall survival in both the verification cohort (area under the receiver operating characteristic curve [AUROC] for 1-, 3-, and 5-year survival: 0.82, 0.80, and 0.78) and the independent validation cohort (AUROC for 1- and 3-year survival: 0.80 and 0.83). Consistent AUROC was observed across tumor stages. CONCLUSION:The 19-gene signature, considering the dynamic shift during HCC progression, may accurately predict survival outcomes in HCC patients as a potential tool for personalized prognosis.

Introduction and Objectives Baseline hepatitis B surface antigen (HBsAg) levels are associated with the likelihood of achieving HBsAg loss which defines a functional cure. However, optimal HBsAg cut-offs for predicting HBsAg loss have not been systematically investigated. Therefore, in this systematic review and meta-analysis, we evaluated the impact of baseline levels of HBsAg on achieving a functional cure in patients with chronic hepatitis B (CHB). Materials and Methods We searched PubMed, Embase, and the Cochrane Library up to December 31, 2023, to identify studies comparing combination therapy with nucleos(t)ide analogues (NAs) and conventional/pegylated interferon (IFN) versus monotherapy. We pooled the proportions of HBsAg loss among studies stratified by different 75th percentile of baseline HBsAg levels and other clinical characteristics. Results We included 24 studies with 3446 participants. At the end of treatment, studies recruiting patients with 75th percentile of baseline HBsAg below 500 and 1000 IU/mL had the highest proportions of HBsAg loss in the combination group, reaching 14 % (95 % CI: 9–21 %) and 17 % (95 % CI: 10–24 %), respectively. One-year IFN-NAs combination treatment achieved a higher proportion of HBsAg loss (9 %, 95 % CI: 6–12 %) than six-month IFN-NAs treatment (1 %, 95 % CI: 0–2 %). Patients with normal alanine transaminase (ALT) had higher HBsAg loss (11 %, 95 % CI: 6–17 %) than those with elevated ALT (4 %, 95 % CI: 2–7 %). Meta-regression indicated a positive association between male percentage in studies and HBsAg loss. Conclusions The optimal baseline HBsAg thresholds would be 500–1000 IU/mL, which represents high-response subpopulations for achieving a functional cure with currently available therapy.

With the widespread application of systemic treatments for hepatocellular carcinoma, liver injury caused by molecular targeted drugs and immune checkpoint inhibitors has become a common clinical problem. The Chinese Society of Hepatology, Chinese Medical Association, organized domestic experts to summarize and analyze adverse liver reactions, as well as advances in the diagnosis and treatment related to systemic therapy for liver cancer, both domestically and internationally. Based on this work, we formulated the "Consensus on the Management of Liver Injury Associated with Targeted Drugs and Immune Checkpoint Inhibitors for Hepatocellular Carcinoma", aiming to provide practical recommendations and decision-making guidance for clinicians in hepatology and related specialties. This guidance focuses on the monitoring, diagnosis, prevention, and treatment of liver injury during targeted and immune checkpoint inhibitor therapy, ultimately helping more liver cancer patients benefit from targeted immunotherapy.

The paradigm shift from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) emphasizes metabolic pathogenesis, yet the efficacy of Traditional Chinese Medicine (TCM) under this framework remains unevaluated. Prior reviews focused on NAFLD with outdated data (<2020), lacking clinical translation tools and methodological standards for TCM systematic reviews and meta-analyses (SRs/MAs). This overview integrates NAFLD criteria, visualizes TCM efficacy via evidence mapping, proposes a methodological framework to standardize TCM SRs/MAs, and focuses on evaluating metabolism-related indicators. Nine databases were searched (from database inception to December 30, 2024) for TCM SRs/MAs in NAFLD. Methodological quality was assessed via AMSTAR-2, PRISMA/PRISMA-CHM, and GRADE. Evidence mapping visualized outcomes (liver enzymes, metabolism) to identify clinical priorities. Standardized reporting guidelines for TCM preparations were adhered to, and a ConPhYMP tool assessment evaluated botanical drugs composition and processing disclosure. Thirty-seven SRs/MAs (35 low/critically low quality) reported trends of reduced ALT (−8.2 U/L, 95% CI: −10.1 to −6.3), improved metabolic parameters (e.g., TG: −0.5 mmol/L), and enhanced B-ultrasound resolution (RR: 1.62), though these findings are limited by methodological flaws and low-quality evidence. Evidence mapping highlighted Xiaoyao Powder and Danning Tablet as top-performing formulas. A methodological framework addressing TCM heterogeneity (formula standardization, dosage) and reporting biases was proposed. This is the first overview integrating NAFLD criteria to visualize TCM-related evidence, offering preliminary observations on potential associations between TCM interventions and metabolic outcomes in NAFLD (interpreted with caution due to low evidence quality). The evidence map and methodological guidelines provide a foundation for standardized future TCM research, while clinical translation of current findings is not recommended due to insufficient high-quality evidence.