Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. In addition to the canonical glutathione peroxidase 4 pathway, ferroptosis suppressor protein 1 (FSP1), also known as apoptosis-inducing factor mitochondria-associated 2, functions as a major glutathione-independent suppressor of ferroptosis. Current evidence indicates that FSP1 restrains lipid peroxidation mainly through the nicotinamide adenine dinucleotide (phosphate) [NAD(P)H]-dependent coenzyme Q10 axis. FSP1 has also been implicated in the noncanonical vitamin K cycle, which further expands its redox role. Emerging studies suggest that liquid–liquid phase separation and membrane repair may broaden the functional landscape of FSP1, although these mechanisms remain less fully defined. We then summarize the multilayer regulation of FSP1 and discuss how it contributes to ferroptosis resistance, tumor adaptation, and therapeutic responses in cancer. Finally, we review current preclinical efforts to target FSP1, with emphasis on small-molecule inhibitors, mechanism-based combinations, candidate biomarkers, and major translational challenges. Together, these observations position FSP1 as an important determinant of ferroptosis resistance in cancer and a promising focus for further mechanistic and translational study.

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 The early detection of hepatocellular carcinoma (HCC) remains a major clinical challenge due to the limited sensitivity and specificity of current biomarkers. This study sought to develop a diagnostic model based on serum exosomal microRNAs (miRNAs) and to elucidate the functional mechanism of a key miRNA, miR-200b-3p, in HCC pathogenesis. AIM To develop and validate a serum exosomal miRNA-based diagnostic model for HCC. METHODS Serum exosomes were isolated from a discovery cohort (68 HCC, 131 non-HCC) and a validation cohort (66 HCC, 135 non-HCC). Candidate miRNAs were identified via next-generation sequencing and machine learning, and validated by quantitative real-time polymerase chain reaction. A diagnostic model was constructed using logistic regression. The role of miR-200b-3p was examined using in vitro functional assays. RESULTS A diagnostic model incorporating three exosomal miRNAs (miR-200b-3p, miR-215-5p, miR-452-5p) and age was established. It showed strong performance in the training set (area under the curve = 0.863, sensitivity = 86.4%, specificity = 76.5%; all P < 0.001). Mechanistically, miR-200b-3p acted as a tumor suppressor by directly targeting phosphoserine aminotransferase 1. Its overexpression inhibited HCC cell proliferation, migration, and invasion (all P < 0.05), while knockdown promoted these phenotypes (all P < 0.05). CONCLUSION This study establishes and validates a non-invasive exosomal miRNA-based diagnostic model for HCC, reveals that miR-200b-3p directly targets phosphoserine aminotransferase 1, and provides mechanistic support for early detection.

ObjectiveTo analyze the clinical and hepatic pathological characteristics of patients with chronic hepatitis B (CHB) alone or with non-alcoholic fatty liver disease (NAFLD), who have normal alanine aminotransferase (ALT) levels.MethodsThe patients with normal ALT levels and pathologically diagnosed CHB alone or in combination with NAFLD were enrolled, the demographic, laboratory, and pathological data were collected and analyzed.ResultsAmong 391 enrolled CHB patients with normal ALT levels, 107 individuals combined with NAFLD. The incidence of significant liver injury (G and/or S ≥ 2) in patients with CHB alone was lower significantly than that of patients with CHB and NAFLD (64.08% vs. 78.50%, P < 0.05), especially by the subgroup analyses in HBeAg positive, male, age > 30 years (P < 0.05). In all patients, who with negative HBcAg expression had lower HBV DNA levels than those with positive HBcAg expression (P < 0.001). Patients with G and/or S ≥ 2 had a higher proportion of HBcAg cytoplasm/cytoplasmic nucleus expression type compared to patients with liver tissue G and S < 2 (32.42% vs. 16.67% in CHB alone, 36.91% vs. 21.74% in CHB + NAFLD, all P < 0.001). Aspartate aminotransferase to ALT ratio index (AAR) demonstrated relatively superior efficacy in diagnosing significant liver fibrosis among patients with CHB and NAFLD, while fibrosis-4 (FIB-4) exhibited superior performance in patients with CHB alone.ConclusionPatients with normal ALT can still demonstrate significant liver tissue damage. The combination of NAFLD will significantly increase the incidence of significant liver injury in patients with CHB, especially in those who are HBeAg positive, male, over 30 years old.

Background and Aims:Hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection are among the leading causes of chronic liver diseases worldwide. Through the same transmission routes, HBV/HCV coinfection is widespread and aggravates liver damage. In this study, we aimed to assess the safety and efficacy of sofosbuvir/velpatasvir (SOF/VEL) and the pre-treatment of tenofovir alafenamide fumarate (TAF) on HBV reactivation in HBV/HCV coinfected patients. Methods:A multicenter, prospective, single-arm, open-label 12-week trial, followed by a 12/48-week observational clinical trial, was conducted. Ninety-six adults with chronic HBV/HCV coinfection were enrolled from May 2021 to December 2024 in thirteen centers in China. Seventy-seven non-cirrhotic patients were included in Group 1 and nineteen compensated cirrhotic patients in Group 2. All subjects were enrolled to receive SOF/VEL once daily for 12 weeks. Non-cirrhotic subjects received TAF once daily for 28 weeks, and compensated cirrhotic subjects received TAF once daily for 64 weeks simultaneously. Statistical significance was set at P < 0.05. Results:At the end of SOF/VEL treatment, the overall sustained virologic response was 97.9%, of which 100% was achieved in Group 2. HCV RNA, HBV DNA, and HBV RNA levels were substantially decreased in all patients. Alanine aminotransferase (ALT) (61.5 vs. 21.9, P < 0.001) and aspartate aminotransferase (AST) (50.8 vs. 25.7, P < 0.001) levels decreased, and albumin (ALB) (42.4 vs. 45.1, P < 0.001) level increased compared to pre-treatment in Group 1 at 12 weeks post-treatment. ALT (64.1 vs. 25.2, P < 0.001), AST (65.7 vs. 29.7, P < 0.001), alkaline phosphatase (ALP) (111.6 vs. 88.2, P < 0.05), and alpha-fetoprotein (AFP) (17.9 vs. 4.7, P < 0.05) levels decreased, and ALB (41.3 vs. 42.5, P = 0.051) and platelet count (PLT) (114.0 vs. 127.2, P = 0.052) levels showed a trend toward increase compared to pre-treatment in Group 2 at 48 weeks post-treatment. Liver stiffness measurement (LSM) (22.6 vs. 12.7, P < 0.01), aspartate aminotransferase to platelet ratio index (APRI) (1.6 vs. 0.6, P < 0.001), and fibrosis-4 index (FIB-4) (4.7 vs. 2.6, P < 0.05) significantly decreased after treatment in Group 2. Two patients in Group 1 with genotype 3 showed HBV reactivation and HCV relapse, respectively. No drug-related adverse events were observed in the study. Conclusions:SOF/VEL effectively achieves a sustained virologic response and improves liver function, with an acceptable safety profile in chronic HBV/HCV coinfected patients, including those with compensated cirrhosis, who achieved modest improvement in non-invasive fibrosis indices. Pre-administration of TAF may mitigates the risk of HBV reactivation in this population.

BACKGROUND & AIMS:The overlap between chronic hepatitis B (CHB) and metabolic dysfunction-associated steatotic liver disease (MASLD) has been growing. This study aimed to explore the impact of CHB and its clinical phases on liver fibrosis/cirrhosis in patients with MASLD. METHODS:We enrolled patients with MASLD who underwent vibration-controlled transient elastography (VCTE) or liver biopsy at 19 centers in China between 2004 and 2025. Logistic regression analyses were conducted to examine the association between CHB and liver fibrosis/cirrhosis. Propensity score matching was used to adjust for potential confounders. RESULTS:A total of 6682 patients with MASLD were included, comprising 3979 VCTE-based cases (351 with concurrent CHB) and 2703 biopsy-proven cases (1811 with concurrent CHB). In the VCTE cohort, patients with MASLD and CHB had higher proportions of significant fibrosis (50.1% vs 33.5%), advanced fibrosis (25.4% vs 10.8%), and cirrhosis (15.7% vs 5.4%) (all P < .001), with similar findings in the biopsy cohort. Multivariate analyses showed that concurrent CHB independently increased the risks of fibrosis/cirrhosis in both cohorts (odds ratios [ORs]: VCTE cohort: 1.98-3.73; biopsy cohort: 1.98-3.37; all P < .001). Under the 2018 American Association for the Study of Liver Diseases criteria, hepatitis B e-antigen-positive immune-active CHB had the highest odds of significant fibrosis, advanced fibrosis, and cirrhosis (OR, 3.27-11.18; P ≤ .001), with elevated odds also observed in gray-zone CHB (OR, 3.05-6.95; P ≤ .001); associations remained similar after propensity score matching and application of the 2025 European Association for the Study of the Liver classification. CONCLUSIONS:Concurrent CHB increased liver fibrosis/cirrhosis risk in MASLD not only in the immune-active phase but also in the gray-zone phase. Patients with MASLD and concomitant active/gray-zone CHB may warrant enhanced noninvasive monitoring and individualized management to mitigate fibrotic progression.

Background and Aims:Liver fibrosis is characterized by the excessive deposition of extracellular matrix, a process primarily driven by activated hepatic stellate cells (HSCs), and currently lacks effective therapy. Cathepsin K (CTSK) exhibits context-dependent roles across organ systems in fibrosis, but its function in liver fibrosis is unclear. This study aimed to investigate the role and underlying mechanisms of CTSK during liver fibrosis. Methods:CTSK expression was analyzed in human fibrotic liver samples via transcriptomic analysis and confirmed in murine fibrosis models. The function of CTSK was investigated in both primary HSCs and LX-2 cells by assessing its effects on cell activation, proliferation, apoptosis, and the underlying signaling pathways following CTSK overexpression. The therapeutic potential was evaluated using an adeno-associated virus serotype 8 to overexpress CTSK in two etiologically distinct murine fibrosis models. Results:CTSK was upregulated in activated HSCs and fibrotic livers. Furthermore, we discovered that it mediates a negative feedback loop to inhibit the TGF-β/Smad pathway via Smad7/Smurf2-dependent TGF-β receptor-I degradation, thereby suppressing HSC activation and proliferation. CTSK also induced mitochondrial apoptosis through Bax/Bcl-2 imbalance and caspase-3 activation. Together, these actions contribute to the anti-fibrotic effect of CTSK. Notably, adeno-associated virus serotype 8-mediated CTSK overexpression attenuated liver fibrosis across multiple murine models. Conclusions:Our study demonstrates that elevated CTSK functions as an endogenous protective factor that attenuates liver fibrosis. CTSK mediates negative feedback inhibition of the TGF-β pathway while concurrently promoting the mitochondrial apoptosis pathway. The dual anti-fibrotic mechanisms identify CTSK as a promising therapeutic target for liver fibrosis.

Chronic liver disease (CLD)-related thrombocytopenia can limit the feasibility of invasive procedures. Recombinant human thrombopoietin (rhTPO) has demonstrated a favorable safety profile without hepatotoxicity. We evaluated the efficacy and safety of rhTPO in patients with CLD-related thrombocytopenia who were undergoing elective invasive procedures. In this multicenter, randomized (2:1), double-blind, placebo-controlled phase III trial, 120 adult Chinese patients with CLD-related thrombocytopenia (platelet count < 50 × 109/L) received rhTPO (n = 80) or placebo (n = 40) once daily for up to 5 or 7 days. The primary endpoint was the proportion of patients with sustained platelet counts ≥ 50 × 109/L from 24 h before invasive procedure to 7 days post-procedure, without requiring emergency bleeding management. The primary endpoint was achieved by 85.0% of patients in the rhTPO group versus 12.5% in the placebo group (p < 0.0001). Preoperatively, platelet counts ≥ 50 × 109/L were achieved in 92.5% and 20.0% of patients in the rhTPO and placebo groups, respectively (p < 0.0001). Platelet transfusion was avoided in 92.5% of rhTPO-treated patients versus 25.0% of placebo-treated patients (p < 0.0001). The median duration of platelet counts ≥ 50 × 109/L was significantly longer with rhTPO than with placebo (21.0 vs. 3.0 days, p = 0.0007). Treatment-related treatment-emergent adverse events (TEAEs) occurred in 12.5% of patients in both the rhTPO and placebo groups. No treatment-related serious adverse events were reported. Overall, rhTPO was effective and well tolerated in patients with CLD-related thrombocytopenia and may represent a viable therapeutic option for those undergoing elective invasive procedures. Trial Registration: www.chinadrugtrials.org.cn: number CTR20230919.

The gut microbiota is crucial in maintaining host health and liver function. Fecal microbiota transplantation (FMT) has shown promising potential in treating chronic liver diseases. To help clinicians quickly master and standardize the clinical application of FMT for chronic liver disease, the Liver Related Digestive Diseases Group of the Chinese Society of Hepatology of the Chinese Medical Association has developed the "Expert Consensus on the Clinical Application of FMT for Chronic Liver Disease." This consensus addresses the key aspects of FMT, including the indications, contraindications, efficacy, safety, donor selection, transplantation routes, precautions, and the prevention and management of adverse reactions for chronic liver conditions, such as chronic hepatitis, cirrhosis, and liver cancer, thereby offering reference and guidance to clinicians implementing FMT in the treatment of chronic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global epidemic, with a rapidly increasing burden among children and adolescents in China. This alarming trend is primarily driven by profound lifestyle shifts. Unlike earlier perceptions of pediatric MASLD as relatively benign, pediatric-onset MASLD is now recognized as a progressive condition associated with liver fibrosis, cirrhosis, cardiometabolic comorbidities, and elevated risks of hepatocellular carcinoma and early mortality. In China, this escalating burden is compounded by regional disparities, diagnostic challenges, and limited access to pediatric-specific screening and management tools. Yet early-life detection and intervention present a critical window to mitigate long-term liver-related and systemic health consequences. This review synthesizes the latest epidemiological data, screening strategies, diagnostic innovations, and therapeutic approaches for pediatric MASLD in the Chinese context. By integrating emerging evidence with national public health priorities, we aim to inform actionable policies and tailored intervention strategies to confront this growing epidemic.

Background and Aims:Heme oxygenase 1 (HO-1) has an influential yet insufficiently investigated effect on Sirtuin 1 (SIRT1), a histone deacetylase activated by nicotinamide adenine dinucleotide, which may impact the transforming growth factor-β (TGF-ß)/Smad3 pathway in nonalcoholic fatty liver disease (NAFLD)-related liver fibrosis. This study aimed to elucidate the regulation of NAFLD-related liver fibrosis induced by HO-1 through the SIRT1/TGF-ß/Smad3 pathway. Methods:HO-1 induction and inhibition were established in C57BL/6J mice fed a methionine- and choline-deficient (MCD) diet. Additionally, wild-type mice were fed either a normal diet or an MCD diet. Hematoxylin and eosin, Masson's trichrome, and Sirius Red staining were used to assess hepatic steatosis, inflammation, and fibrosis. In vitro, plasmid overexpression and small interfering RNA silencing of HO-1 were performed in LX-2 cells. Cell viability was assessed using the Cell Counting Kit-8, and apoptosis was evaluated via terminal deoxynucleotidyl transferase dUTP nick-end labeling and immunofluorescence. Flow cytometry was employed to assess apoptosis and reactive oxygen species production. Western blot and real-time quantitative reverse transcription polymerase chain reaction were used to analyze the mRNA and protein expression of genes related to HO-1, SIRT1, the TGF-ß signaling pathway, and fibrosis. Results:MCD-fed mice developed significant liver damage, including steatosis, inflammatory infiltration, and pericellular fibrosis. Zinc protoporphyrin treatment exacerbated these conditions. Corroborating these findings, silencing HO-1 in LX-2 cells increased the expression of fibrosis-related genes. Furthermore, HO-1 overexpression not only increased SIRT1 expression but also reduced the activity of key regulatory factors in the TGF-ß signaling pathway, suggesting a potential interaction between HO-1 and the SIRT1/TGF-ß pathway. Conclusions:HO-1 inhibits the activation of the TGF-ß/Smad3 pathway in NAFLD-related liver fibrosis through SIRT1. These findings provide insights into new therapeutic strategies for treating NAFLD-associated liver fibrosis.

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.

BACKGROUND:This retrospective multicenter study is aimed at evaluating the diagnostic accuracy and influence factors of serum des-gamma-carboxy prothrombin (DCP) as a diagnostic biomarker of hepatocellular carcinoma (HCC). METHODS:Clinical data were collected from 4555 subjects with DCP tests, composed of primary liver cancer (PLC), metastatic liver cancer (MLC), chronic hepatitis (CH), liver cirrhosis (LC), benign liver diseases (BLD), biliary tract diseases (BTD), non-liver cancers (NLC), and non-liver benign diseases (NLBD). The clinical data collected included medical history, treatment records, various serum tests, and imaging examination. RESULTS:Serum DCP was measured with Abbott agents in each center. In HCC, serum DCP concentration was at 9086.00 ± 366.10 mAU/mL, higher than that in other diseases (p < 0.05). At 40.00 mAU/mL recommended by instruction, positive rates of serum DCP were at 85.11% in HCC, 30.12% in intrahepatic cholangiocellular carcinoma (ICC), 31.65% in MLC, 13.95% in BLD, 18.14% in CH, 27.87% in LC, 15.75% in BTD, 35.29% in NLC, and 20.00% in NLBD. In this study, the diagnostic specificity of serum DCP in HCC was affected by liver function. In HCC, serum AFP concentrations also increased compared to non-HCC diseases (p < 0.05), but specificity varied with agents from different providers. Serum DCP decreased after the surgical removal of HCC, but remained elusive in systemic treatment. CONCLUSION:Serum DCP may serve as an optimal biomarker for the diagnosis of HCC, but its accuracy appears influenced by liver function; attention needs to be paid to the liver function of patients for false positivity.