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.

Background Wilson disease (WD) is a rare inherited copper metabolism disorder with variable prevalence worldwide. Many regions lack reliable data, leading to underestimation of burden. WD presents with hepatic, neurological, and psychiatric symptoms, but mental health impacts and economic costs are often overlooked. Methods We systematically searched PubMed up to July 2025 for studies reporting WD prevalence, clinical features, quality of life, or economic burden. Disability-adjusted life years (DALYs) were estimated, and temporal trends were analyzed. Meta-analyses pooled epidemiological and clinical data. Forecast models predicted future prevalence and costs. Results A total of 136 studies were included. Prevalence varied, being higher in Southern Europe and parts of Asia, but lower in Northern/Eastern Europe. Rising prevalence was observed in Morocco, South Korea, Spain, and Germany, likely due to improved recognition. Forecasts suggest a gradual global increase through 2030. WD mainly affects young individuals (mean age 19.9 years), with hepatic involvement in 72% and acute liver failure in 31%. Overall mortality was 14%. Mental health complications were frequent, with depression in 47.7% and anxiety in 40%. DALYs have risen globally since the 1970s, with China, the U.S., and Poland projected to carry the heaviest future burden. Economic costs are substantial, particularly in the U.S., where annual hospitalization per patient may exceed USD 60,000. Conclusion WD imposes significant clinical, psychological, and economic burdens worldwide. Improved early diagnosis, standardized treatment, and comprehensive care are needed to reduce morbidity, enhance quality of life, and lower healthcare costs.

IntroductionAcute-on-chronic liver failure (ACLF) is a highly lethal clinical syndrome with limited effective therapeutic options. Urine-derived stem cells (USCs) represent a non-invasive and readily accessible cell source, but whether USCs obtained from patients with severe liver dysfunction retain therapeutic and immunomodulatory potential remains unclear.MethodsTo address this question, USCs derived from ACLF patients (LF-USCs) were evaluated in a Concanavalin A (Con A)-induced immune-mediated acute liver injury mouse model. Hydrogel-encapsulated LF-USCs were transplanted, and therapeutic efficacy was assessed by survival analysis, serum biochemical parameters, histological examination, and inflammatory cytokine profiling.ResultsTransplantation of hydrogel-encapsulated LF-USCs significantly improved mouse survival, reduced serum transaminase levels, and alleviated hepatocellular necrosis (p < 0.05). At the mechanistic level, LF-USC treatment was associated with decreased systemic inflammatory cytokine levels, attenuation of intrahepatic inflammatory injury, and dynamic modulation of macrophage-associated inflammatory signatures.DiscussionThese findings demonstrate that functionally competent USCs can be successfully obtained from ACLF patients and highlight their potential as a readily accessible autologous cell source for immune modulation and liver tissue repair in immune-mediated acute liver injury.

BACKGROUND:Sphingolipids play an important role in the development of multiple metabolic disease. However, no study explored the impact of bilirubin on sphingolipid metabolism in human. This study aims to investigate the plasma sphingolipid profiles and their association with blood lipids in mild hyperbilirubinemia (Gilbert's syndrome; GS) individuals. METHODS:This cross-sectional study enrolled 224 participants including 112 individuals with GS and 112 age- and gender-matched healthy controls. Liquid chromatography-mass spectrometry was employed to quantify 53 plasma sphingolipid metabolites in a subset of 55 GS and 55 age- and gender-matched healthy controls. OPLS-DA model was constructed using SIMCA 14.1 software to identify distinct plasma sphingolipid metabolites between two groups. RESULTS:The median age of 224 subjects was 35 years, with males comprising 29.5%. The GS group exhibited higher levels of total bilirubin and high-density lipoprotein cholesterol, along with lower levels of triglycerides (all P < 0.05). Analysis of plasma sphingolipid revealed significant differences in 14 sphingolipids between two groups. Compared to the healthy control group, the GS group had lower levels of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/25:0), Cer(d18:1/26:0), Cer(d18:2/16:0), CerP(d18:1/22:0), HexCer(d18:1/22:0), HexCer(d18:1/24:1), HexCer(d18:1/24:0), LacCer(d18:1/16:0), as well as higher levels of CerP(d18:1/12:0), LacCer(d18:1/24:0), sphingosine-1-phosphate, and sphinganine (all P < 0.05). Correlation analysis of 110 subjects indicated that Cer(d18:1/25:0), Cer(d18:1/26:0), Cer(d18:2/16:0), CerP(d18:1/22:0), HexCer(d18:1/22:0), HexCer(d18:1/24:0) were positively correlated with total cholesterol. Additionally, sphinganine was positively correlated with high-density lipoprotein cholesterol and sphingosine 1-phosphate was negatively correlated with triglycerides (all P < 0.05). CONCLUSION:This study demonstrated that plasma ceramide levels decreased in Gilbert's syndrome, which correlates with a favorable blood lipid profile.

Background and Aims: Tenofovir alafenamide (TAF) has demonstrated comparable efficacy to tenofovir disoproxil fumarate (TDF), with improved renal and bone safety, in Chinese participants with chronic hepatitis B enrolled in two Phase 3 trials. This study aimed to evaluate the long-term virologic efficacy, serological and biochemical responses, resistance, and renal and bone safety of TAF over eight years in this population. Methods: Participants completing the threeyear double-blind phase were eligible to receive open-label TAF 25 mg/day for up to an additional five years (totaling eight years). Analyses of viral suppression (HBV DNA < 29 IU/mL), alanine aminotransferase normalization, serological responses, resistance surveillance, and safety outcomes were conducted. Results: Among 334 enrolled participants, 212 of 227 participants randomized to TAF continued open-label TAF (TAF-TAF), and 99 of 107 participants on TDF switched to open-label TAF (TDF-TAF). At Year 8, 79.3% (180/227) and 78.5% (84/107) of participants in the TAF-TAF and TDF-TAF groups, respectively, achieved viral suppression (missing = failure); rates increased to 95.2% (180/189) and 95.5% (84/88) when excluding missing data. Alanine aminotransferase normalization rates remained high and comparable between groups. Serologic response rates continued to increase over time, with higher rates observed in the TAF-TAF group. Estimated glomerular filtration rate (by Cockcroft-Gault) and hip/spine bone mineral density remained stable in the TAF-TAF group through eight years; the small declines in these renal and bone parameters observed during doubleblind TDF treatment improved after switching to open-label TAF. No resistance to TAF was detected. Conclusions: Longterm TAF treatment demonstrated durable virologic efficacy, sustained biochemical and serological responses, and favorable renal and bone safety over eight years in Chinese participants with chronic hepatitis B.

Acute-on-chronic liver failure (ACLF) is a severe syndrome in patients with chronic liver disease, marked by rapid multi-organ failure and high short-term mortality. Managing ACLF requires intensive care, but standardized global guidelines were previously lacking. The APASL ACLF Research Consortium (AARC) developed this position paper to establish a unified, evidence-based consensus for its critical care management. A global collaboration of 109 experts employed a systematic methodology to address key aspects of ACLF care. Sections were drafted by specialist teams, with recommendations developed using the GRADE system. Draft statements underwent iterative review and refinement, followed by an expert panel consensus process consisting of open show-of-hands voting during the APASL Annual Conference in March 2025 in Beijing and a subsequent anonymous online voting round. The consensus delivers 104 position statements. Key recommendations include using prognostic scores (AARC, CLIF-C ACLF, GIC) for ICU transfer and treatment decisions, and aggressively managing precipitating factors or complications like infections. It details organ-specific support for liver, kidney, and brain failure, advocating for early, targeted antibiotics and careful fluid management. The role of bridging therapies (plasma exchange, artificial liver systems) and nutritional support is emphasized. For transplantation, the guidelines provide criteria for patient selection and timing, particularly for alcohol-related ACLF. The APASL ACLF Beijing Position Paper provides a comprehensive, standardized framework for managing critically sick ACLF patients. Integrating multidisciplinary expertise and current evidence, these guidelines aim to optimize care, inform clinical decisions, and improve survival for this high-risk population. As a few recommendations are supported predominantly by data from different continents, they should therefore be interpreted in local contexts.

The heterogeneity in ACLF definitions proposed by different expert associations worldwide has led to variations in clinical phenotypes and prognosis. This study proposes a new approach for a unified definition based on the type of organ failure within the first week of disease onset.This prospective cohort study collected clinical data from hospitalized ACLF patients presenting with liver failure (total bilirubin ≥ 5 mg/dL, INR ≥ 1.5) across four liver centers in China. Patients with liver failure within the first week of onset were classified as Type I ACLF, while those with concurrent extrahepatic organ failure were categorized as Type II ACLF. We compared the clinical characteristics and prognosis of Type I and Type II ACLF patients, as well as the inclusivity of these classifications within existing mainstream ACLF definitions.A total of 846 patients were included in the analysis population. Type I ACLF occurred in 86.9% of cases, primarily in patients with non-cirrhotic chronic liver disease (34.3%) or compensated cirrhosis (48.6%), while Type II ACLF, observed in 13.1% of cases, predominantly developed in patients with cirrhosis (73%) (P < 0.001). Mortality rates at 28 and 90 days were significantly higher in Type II ACLF patients (43.2% and 52.3%) compared to those with Type I ACLF (15.8% and 24.9%) (P < 0.001). Patients with Type I ACLF met the APASL criteria more frequently (82.9%), whereas those with Type II ACLF more often met the EASL criteria (69.4%). For predicting the 90-day prognosis in Type I ACLF, the COSSH-ACLF II score achieved the highest AUROC at 0.788 (95% CI: 0.749-0.828). In Type II ACLF, the CLIF-C OF score provided the highest AUROC for predicting 90-day mortality, at 0.902 (95% CI: 0.840-0.964), outperforming the MELD, MELD-Na, and COSSH-ACLF II scores (P < 0.05) and showing no significant difference when compared to the CLIF-C ACLF score (0.872 [95% CI: 0.791-0.953], P = 0.426).This new clinical classification approach takes into account the characteristics defined by both Eastern and Western ACLF, and is expected to improve the comparability and interpretability of data in global studies, enhancing global understanding and management of ACLF.

BackgroundLow skeletal muscle mass is an independent risk factor for increased mortality in patients with acute-on-chronic liver failure (ACLF). However, no study has evaluated the temporal changes in muscle mass during the course of ACLF. Therefore, this study aimed to investigate the dynamic changes in muscle mass and their prognostic role in patients with ACLF.MethodsA retrospective analysis was conducted on consecutive patients with ACLF who underwent two or more abdominal computed tomography examinations within 90 days of admission. The percentage change rates of the skeletal muscle index at the third lumbar vertebra (L3-SMI) were calculated as (L3-SMIfinal - L3-SMIinitial)/(L3-SMIinitial) × 100%.ResultsA total of 154 patients with ACLF were included. During the course of ACLF, the percentage change rates of L3-SMI at 2–7, 8–14, 15–30, 31–60, and 61–90 days were − 0.83 ± 4.43, −3.76 ± 4.40, −7.30 ± 5.89, −10.10 ± 7.45, and − 5.53 ± 9.26, respectively. Significant reductions in L3-SMI were noted in patients with severe conditions compared to other patients at 2–7 days and 15–30 days. Moreover, the rate of decrease in L3-SMI in patients with a lower respiratory quotient (RQ) was significantly greater than that in patients with a normal RQ at 2–7 days and 15–30 days. Additionally, high muscle loss (HR 2.059; 95% CI 1.122–3.780, p = 0.020), rather than pre-existing sarcopenia (HR 1.430; 95% CI 0.724–2.826, p = 0.303) at baseline, was independently associated with 90-day mortality.ConclusionDeterioration in muscle mass is associated with disease severity and poor nutritional status and serves as a more effective predictor of adverse short-term outcomes in patients with ACLF. These findings underscore the importance of dynamic evaluation of muscle loss and emphasize the necessity of reversing muscle loss in patients with ACLF.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease with complex pathogenesis. Autophagy is involved in the occurrence and development of MASLD. Naringin is a flavonoid compound with anti-inflammatory and anti-oxidation effects. This study is to investigate the impact of naringin on autophagy in an organoid model of tissue-engineered fatty liver (TEF). METHODS AND RESULTS:Human hepatocytes were cultured on a rat liver biomatrix scaffold and perfused with fat-supplemented medium to establish 3D MASLD models. Naringin was treated for 3 days. Histopathological changes were determined by oil red O and hematoxylin-eosin staining; organelle morphology was examined by scanning electron microscopy and transmission electron microscopy (TEM); the expression of autophagy-related factors was analyzed by qPCR and Western Blot. Hepatocyte injury was determined by terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) staining, cell counting and lactate dehydrogenase (LDH) detection. The results showed naringin significantly improved liver injury in the MASLD model, as evidenced by increased cell viability, reduced lipid accumulation and LDH release. TEM revealed the presence of autophagosomes in naringin-treated hepatocytes. Naringin upregulated the expression of autophagy-related proteins (LC3, ATG5, ATG7) and promoted the LC3-II/LC3-I ratio, indicating enhanced autophagic flux. Furthermore, naringin regulated the mTOR-ULK1 signaling pathway by downregulating p-mTOR and p-ULK1 (Ser757) and upregulating Beclin1. Autophagy inhibitors (3-Methyladenine and SBI-0206965) attenuated the protective effects of naringin, confirming the role of autophagy in hepatocyte protection. CONCLUSION:Naringin mitigates liver damage in the TEF model by enhancing autophagy via mTOR-ULK1 pathway, highlighting its potential as a therapeutic agent for MASLD.

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.

Very recently, we creatively put forward a new classification for ACLF patients, which lays the foundation for the establishment of prognostic model that can accurately predict the prognosis of ACLF patients. Herein, we found: galectin-3 levels were higher in type A ACLF patients compared to those of type B patients; galectin-3 expression was closely correlated with TBil, PTA/INR and MELD; galectin-3 is an independent predictive factor for rapid progression in ACLF, and exhibited superior predictive value for the prognosis of type A ACLF patients than MELD score; and the survival rate was remarkably higher in ACLF patients with lower galectin-3 expression. Collectively, galectin-3 can be considered as a non-invasive biomarker to predict the prognosis of ACLF patients with new typing. Our findings help advance the time window of prognosis prediction for type A and type B ACLF patients from 4 weeks to the baseline, thereby identifying ACLF patients who really need liver transplantation earlier and improving the survival of ACLF patients.

Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of liver transplantation. There have been various definitions proposed worldwide. The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set in 2004 on ACLF was published in 2009, and the "APASL ACLF Research Consortium (AARC)" was formed in 2012. The AARC database has prospectively collected nearly 10,500 cases of ACLF from various countries in the Asia-Pacific region. This database has been instrumental in developing the AARC score and grade of ACLF, the concept of the 'Golden Therapeutic Window', the 'transplant window', and plasmapheresis as a treatment modality. Also, the data has been key to identifying pediatric ACLF. The European Association for the Study of Liver-Chronic Liver Failure (EASL CLIF) and the North American Association for the Study of the End Stage Liver Disease (NACSELD) from the West added the concepts of organ failure and infection as precipitants for the development of ACLF and CLIF-Sequential Organ Failure Assessment (SOFA) and NACSELD scores for prognostication. The Chinese Group on the Study of Severe Hepatitis B (COSSH) added COSSH-ACLF criteria to manage hepatitis b virus-ACLF with and without cirrhosis. The literature supports these definitions to be equally effective in their respective cohorts in identifying patients with high mortality. To overcome the differences and to develop a global consensus, APASL took the initiative and invited the global stakeholders, including opinion leaders from Asia, EASL and AASLD, and other researchers in the field of ACLF to identify the key issues and develop an evidence-based consensus document. The consensus document was presented in a hybrid format at the APASL annual meeting in Kyoto in March 2024. The 'Kyoto APASL Consensus' presented below carries the final recommendations along with the relevant background information and areas requiring future studies.

ETHNOPHARMACOLOGICAL RELEVANCE:The ameliorative effect of traditional Chinese medicine (TCM) on hepatic fibrosis has been widely recognized and researched, but studies on the mechanism of action have been hampered by its complex composition, which requires more in-depth studies to elucidate why and how TCM works. The theory of TCM believes that the liver is closely related to blood circulation, and hepatic fibrosis is caused by blood stagnation. Taohong Siwu Decoction (THSW) is a classic formula for nourishing and invigorating blood and has been used clinically for centuries. Current evidence has demonstrated its ameliorative effect on hepatic fibrosis, but the exact mechanism of action remains unclear. AIM OF THE STUDY:Exploring the possible mechanism of the anti-hepatic fibrosis effect of THSW by proteomics and validating with in vivo and in vitro studies. MATERIALS AND METHODS:The carbon tetrachloride (CCl4)-induced fibrosis model was conducted in mice and treated with THSW in vivo with colchicine as the positive control. Then serum biomarker alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histopathological analysis were evaluated to examine the effects of THSW. And hepatic fibrosis indicators alpha-smooth muscle actin (α-SMA) and Collagen Ⅰ (Col-Ⅰ) were detected by western blotting, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Additionally, the 4D Label-free quantitative proteomic analysis of liver samples was applied. In vitro, erastin-induced BRL-3A cells, a rat hepatocyte line, were performed as a hepatocyte ferroptosis model and treated with or without drug-containing serum of THSW. Finally, molecular docking was used to verify the binding ability of the main components of THSW to potential targets. RESULTS:THSW treatment significantly ameliorated serum ALT, AST, hydroxyproline (Hyp) content, α-SMA and Col-Ⅰ mRNA expression in fibrosis mice. Further results showed that THSW decreased the malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE) content and increased the glutathione (GSH) content of liver tissue. Notably, proteomic analyses have identified 294 differentially expressed proteins in the THSW-treated group compared to the model group, with 97 proteins up-regulated and 197 down-regulated. Functional analysis of these differential proteins highlights the significant roles of inflammation and oxidative stress. Further validation in vivo and in vitro, THSW significantly improved the protein expression of glutathione S-transferase M1 (GSTM1), down-regulate the expression of transferrin receptor (TFRC), and kelch-like ECH-associated protein 1(Keap1) proteins, and promote the metabolism of GSH. Especially it reduced serum iron levels, increased total iron binding capacity, and up-regulated recombinant solute carrier family 7, member 11 (SLC7A11), nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPX4) protein expression, suggesting the inhibition of hepatocyte ferroptosis. In addition, the molecular docking results showed that its main components, amygdalin, hydroxysafflor yellow A, paeoniflorin, and albiflorin, possessed good binding ability with Keap1. CONCLUSIONS:THSW represents a novel therapeutic effect on hepatic fibrosis in mice, accompanied by inhibiting hepatocyte ferroptosis. Mechanically, THSW may regulate the glutathione metabolic pathway and TFRC expression through its main ingredients, such as amygdalin, hydroxysafflor yellow A, paeoniflorin, and albiflorin, thereby inhibiting hepatocyte ferroptosis.

Most recently, exosomes (Exos) derived from 3D-cultured cells exhibit great advantages over 2D-Exos. Nevertheless, it remains to be explored whether 3D (tissue engineering liver) exosomes are superior to 2D-Exos in protecting mice from acute liver injury (ALF) and the underlying mechanism. Herein, we demonstrated that 3D-Exos manifested higher yields, protein concentration and RNA content compared to 2D-Exos. Remarkably, 3D-Exos exhibited superior hepatoprotection against ALF, as shown by reduced TBiL levels, improved liver architecture and alleviated inflammation. According to miRNA sequencing and KEGG enrichment analysis, the differentially expressed genes between 2D- and 3D-Exos could be enriched in "Hippo-YAP" and "autophagy" pathways. Moreover, the levels of YAP/TAZ and autophagy markers were more elevated in 3D-Exos-treated mice. Specifically, inhibiting YAP and autophagy signaling destroyed the hepatoprotection conferred by 3D-Exos. Collectively, 3D-Exos exert superior hepatoprotection against ALF by up-regulating YAP and autophagy signaling. Our finding provides powerful support for administering 3D-Exos to treat ALF efficiently.