Background/Aims
Dysregulated cholesterol metabolism is a hallmark of hepatocellular carcinoma (HCC) that drives tumor initiation and progression. However, clinical targeting of cholesterol metabolism has yielded limited benefits due to stringent feedback in tumor cells. Identifying a central mediator capable of restoring cholesterol homeostasis within the cell’s intrinsically fine-tuned regulatory framework is urgently needed.
Methods
We integrated a proteomic dataset from patients with cholesterol-dysregulated HCC into a global cholesterol metabolic regulatory network to identify potential therapeutic targets for disrupted cholesterol homeostasis. The prognostic significance of the candidate targets was further validated in an independent cohort through immunohistochemistry. Functional and mechanistic studies were conducted in vitro using HCC cell lines and in vivo using mouse models. The pharmacological efficacy of the candidate agent was evaluated in both subcutaneous and orthotopic HCC mouse models.
Result s:
ERLIN1, a pivotal regulator of cholesterol metabolism reprogramming, was identified as an independent favorable prognostic indicator in HCC. ERLIN1 constrains HCC progression both in vitro and in vivo by stabilizing the INSIG1–SCAP–SREBP2 axis and maintaining the metabolic balance of intracellular cholesterol. Under hypoxia, impaired FIH-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 enhances ASB11-mediated ERLIN1 degradation. Pharmacological targeting of this axis using zoledronic acid (ZoA) attenuated HCC progression by weakening the ASB11–ERLIN1 interaction and restoring cholesterol homeostasis.
Conclusions
ERLIN1 represents a druggable metabolic vulnerability in cholesterol-dysregulated HCC. Targeting the ASB11–ERLIN1 axis with the clinically approved ZoA reestablishes cholesterol homeostasis and offers a promising therapeutic strategy to overcome the current limitations of cholesterol-targeted HCC therapies.
Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease and hepatocellular carcinoma (HCC). Advances in surgical techniques and immunosuppressive regimens have markedly improved early post-transplant survival. However, long-term outcomes remain compromised by HCC recurrence, chronic rejection, metabolic complications, and de novo malignancies. Recurrence of HCC after LT remains a major clinical challenge, with available prognostic models providing limited accuracy in risk stratification. Simultaneously, systemic therapies for unresectable HCC have rapidly advanced, particularly with immune checkpoint inhibitors (ICIs), providing new opportunities and unique challenges in transplant settings. With ICIs carrying a risk of acute and potentially fatal rejection and lacking controlled data on efficacy or safety in the post-transplant setting, tyrosine kinase inhibitors currently represent a standard option for post-transplant recurrence. Novel biomarkers, such as donor-derived cell-free DNA and the gut microbiome, are emerging as potential tools to refine risk stratification and guide immunosuppression. Furthermore, innovative immunotherapies, including oncolytic viruses and mRNA vaccines, are being explored as tumor-specific approaches. Collectively, these advances may reshape future management of LT recipients.
Hepatitis B virus (HBV) remains a major cause of chronic liver diseases, especially in the Asia-Pacific region. In recent decades, coinfection with hepatitis C virus (HCV) and coexistence with metabolic dysfunction-associated steatotic liver disease (MASLD) have emerged as significant clinical concerns among HBV-infected subjects. Although global HBV vaccination programs and curative therapies for HCV have led to a marked decline in HBV/HCV coinfection, MASLD is rapidly becoming the predominant comorbidity due to the global surge in metabolic risk factors. HBV/HCV coinfection typically results in more severe liver damage, with unique challenges in antiviral treatment and risk of HBV reactivation post-HCV clearance. In contrast, HBV/MASLD overlap demonstrates complex metabolic-viral interactions that may influence viral replication, hepatitis B surface antigen seroclearance, fibrosis progression, and risk of hepatocellular carcinoma. This review critically compares the epidemiology, clinical outcomes, and management strategies of HBV patients with concurrent HCV or MASLD, while addressing current research gaps and proposing directions for future investigations.
Hepatocellular carcinoma (HCC) imposes a major health and economic burden worldwide, with disproportionate effects in low- and middle-income countries (LMICs). Surveillance in high-risk populations, typically using semiannual ultrasound and alpha-fetoprotein (AFP) testing, has been shown to be cost-effective by enabling earlier detection and improving survival. Yet, its overall value is reduced by poor adherence and the limited sensitivity of ultrasound, particularly in patients with metabolic-associated steatotic liver disease. Emerging approaches—including abbreviated MRI, multi-biomarker models (e.g., GALAD), and liquid biopsy assays such as methylated DNA markers—demonstrate greater diagnostic accuracy and potential economic advantages compared with conventional methods. Integration of artificial intelligence (AI) into imaging may further enhance efficiency and reduce downstream costs. Moving toward precision surveillance, guided by individualized risk stratification that incorporates etiology, fibrosis stage, and molecular profiles, can optimize allocation of resources and maximize cost-effectiveness at the population level. Interventions to improve adherence, including mailed outreach and behavioral economic incentives, have shown both clinical benefit and cost savings, underscoring the role of implementation science. Because socioeconomic disparities influence both access and outcomes, economic models must explicitly address equity to achieve sustainable impact. Future research should prioritize prospective trials that evaluate not only clinical performance but also the real-world cost-effectiveness of novel technologies and stratified surveillance strategies. For LMICs, adapting proven models into affordable, context-appropriate programs is essential. By combining prevention, precision risk assessment, innovative technologies, and equitable implementation, HCC surveillance can deliver both clinical and economic value, reducing the global burden of disease.
Daeseong Kim, Nam Suk Sim, Seonjeong Woo, Min Hwan Kim, Choong-kun Lee, Seung Soo Hong, Sung Hyun Kim, Ho Kyoung Hwang, Chang Moo Kang, Woo Jung Lee, Jung Hyun Jo, Taek Chung, Sohyun Hwang, Beodeul Kang, Jung Sun Kim, Chang-Il Kwon, Sangwoo Kim, Hong Jae Chon, Chang Gon Kim, Young Nyun Park, Hye Jin Choi
Received September 9, 2025 Accepted December 24, 2025 Published online December 26, 2025
Background & Aims Biliary tract cancer (BTC) is a rare malignancy with poor prognosis. We investigated genomic determinants of clinical benefit from gemcitabine, cisplatin, and nab-paclitaxel (GAP) versus gemcitabine and cisplatin (GC) in advanced BTC.
Methods Clinical and genomic data using TruSight Oncology 500 were analyzed from patients treated with GAP (N=198) or GC (N=89) as first-line therapy.
Result s: With a median follow-up of 33.0 months, GAP modestly improved progression-free survival (PFS) (hazard ratio [HR]=0.764, 95% confidence interval [CI]=0.591–0.989) without significant overall survival (OS) difference compared to GC. Genomic profiling revealed frequent alterations in TP53 (35.2%), KRAS (16.4%), SMAD4 (10.5%), and TNFRSF14 (10.5%), involving RTK/RAS (44.3%), TP53 (41.8%), and PI3K (20.2%) pathways. Single-gene mutations did not predict treatment benefit. However, pathway-level analysis identified PI3K pathway activation as significantly associated with inferior PFS (HR=2.148, 95% CI=1.478–3.124) and OS (HR=2.096, 95% CI=1.413–3.109) in patients receiving GAP, an effect not observed with GC. Importantly, GAP conferred clinical benefit only in patients without PI3K pathway activation, while no survival advantage was seen in those with such alterations (Pinteraction=0.023 for PFS, Pinteraction=0.003 for OS). Similar results were obtained in the independent validation cohort treated with GAP (N=103) or GC (N=64) for BTC.
Conclusion Genomic profiling using next-generation sequencing identified PI3K pathway activation as key molecular determinant that differentiates patient outcomes between GAP and GC treatments in advanced BTC.
Background/Aims Natural killer (NK) cell function is generally considered dampened in chronic hepatitis B virus (HBV) infection; however, the NK cell pool exhibits phenotypic and functional heterogeneity, and the antibody-mediated effect of NK cells remains less characterized. This study evaluated the dynamic changes in antibody-mediated NK cell responses and the involvement of distinct NK subsets across disease stages and during antiviral treatment.
Methods A T-cell receptor-like antibody specific for the HBV core 18–27 peptide (cTCRL-Ab) was used to determine the antibody-mediated effect of NK cells, and an array of NK cell surface markers were analyzed in cross-sectional and longitudinal cohorts of patients with chronic HBV infection. Single-cell RNA sequencing (scRNA-seq) was performed to identify the heterogeneity of NK subsets.
Result s: The cTCRL-Ab enabled the detection of NK cell cytolytic activity and IFNγ production. Notably, cTCRL-Ab-mediated NK cell responses were compromised in chronically HBV-infected patients, particularly in those receiving pegylated interferon-α (Peg-IFNα), which was associated with the downregulation of CD16 expression. Correspondingly, Peg-IFNα inhibited cTCRL-Ab-mediated NK cell function by reducing CD16 expression in vitro. scRNA-seq revealed that CD16 downregulation occurred mainly within a dysfunctional CD16hi NK subset exhibiting exhaustion properties. In contrast, an activated CD16hiNK subpopulation (CX3CR1⁺KLRC2⁻CD16hi) with high cytotoxicity was enriched in patients who experienced favorable treatment responses. Furthermore, the intrahepatic CX3CR1+KLRC2-CD16hisubset tended to exhibit functional restoration in HBsAg loss individuals.
Conclusions Our data contribute to the understanding of antibody-mediated responses of NK cells in chronic HBV infection, and highlight a previously unappreciated functional CX3CR1+KLRC2-CD16hiNK subset as a potential therapeutic target.
Background & Aims Previous studies have identified a substantial degree of agreement between the non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) populations, but the same notion may not apply to normal-weight patients with a lower cardiometabolic risk burden. This study aims to investigate the CMRF distributions between normal-weight and overweight/obese MASLD, the agreement between historical NAFLD and MASLD, and to compare the risk of liver-related events (LREs) and all-cause mortality in normal-weight versus overweight or obese MASLD.
Methods This study included participants with steatotic liver disease (SLD) from five cohorts in Hong Kong, South Korea, and the United States. Participants were recruited from settings including both hospitals and communities. Individuals were classified into normal-weight and overweight/obese groups.
Result s: This study included 33,793 participants with SLD from five cohorts, of whom 20,893 and 20,701 patients met the diagnosis of NAFLD and MASLD, respectively. Normal-weight patients with NAFLD demonstrated a lower CMRF distribution compared to those with overweight/obese NAFLD. In the community-based cohorts, the proportions of 0 CMRF ranged from 9.0-26.7% among normal-weight NAFLD, representing the discrepancy between MASLD and NAFLD definitions. Compared with the overweight/obese MASLD, the normal-weight MASLD had increased all-cause mortality (normal-weight vs. overweight/obese, 23.44 and 13.80 per 1000 person-years; p<0.001) but not LREs (2.81 and 2.59 per 1000 person-years; p=0.54) in the HK CDARS cohort.
Conclusions Normal-weight individuals with NAFLD demonstrated a lower distribution of CMRFs, resulting in the incomplete agreement between historical NAFLD and MASLD.
Ethical Compliance For all involved cohorts, the study protocols conformed to the ethical guidelines of the 1975 Declaration of Helsinki and were approved by the appropriate clinical research ethics committee and/or institutional review board, which provided either written consent or a waiver of informed consent.
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Challenges in defining MASLD in lean individuals: the impact of the Fatty Liver Index on phenotypic characterisation Sherlot Juan Song, Yiwei Liu, Vincent Wai-Sun Wong, Terry Cheuk-Fung Yip Gut.2026; : gutjnl-2026-338216. CrossRef
Xinrui Jin, Sherlot Juan Song, Jimmy Che-To Lai, Grace Lai-Hung Wong, Alice Pik-Shan Kong, Nana Peng, Xiang Xiao, Vincent Wai-Sun Wong, Terry Cheuk-Fung Yip
Clin Mol Hepatol 2026;32(1):353-367. Published online December 1, 2025
Background/Aims Previous studies suggest that hypothyroidism is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and its histological severity, but clinical outcome data are largely lacking. We aimed to study the impact of hypothyroidism on liver-related events (LREs).
Methods Patients with MASLD were identified from a territory-wide registry in Hong Kong during 2000–2024. Thyroid status was determined using diagnosis codes and thyroid function tests. The primary outcome, LRE, was defined as a composite of hepatic decompensation, hepatocellular carcinoma, liver transplantation, and liver-related death.
Result s: A total of 20,478 patients with MASLD were included in the final analysis (mean age 56.4±13.2 years; 43.9% male). At baseline, 18,178 (88.8%) patients were euthyroid, 598 (2.9%) were hyperthyroid, and 1,702 (8.3%) were hypothyroid. Compared with euthyroid patients, both hyperthyroidism and overt hypothyroidism were associated with cirrhosis. At a median follow-up of 4.8 years, 179 patients developed LREs, and 26 died from liver disease. Compared with patients with normal serum thyroid-stimulating hormone (TSH) levels of 0.4–4 mIU/L, those with subclinical (4–10 mIU/L; adjusted time-dependent cause-specific hazard ratio [aCSHR], 2.49; 95% CI, 1.51–4.13) and overt hypothyroidism (>10 mIU/L; aCSHR, 4.91; 95% CI, 1.56–15.47) had an increased risk of LREs. Time-dependent, but not baseline, TSH and thyroid status were associated with LRE risk.
Conclusions Subclinical and overt hypothyroidism are associated with an increased risk of LREs in a dose-dependent manner. The association with time-dependent but not baseline thyroid status underscores the importance of thyroid monitoring and suggests that correction of hypothyroidism may mitigate LRE risk.
Le Bich Hang Pham, Taeeung Kim, Seoyoung Kim, Yun Seok Kim, Jiyeon Kim, Kyeongseon Kim, Hyeonwoo Lim, Wan Seob Shim, Byoungmo Kim, So-Yeol Yoo, Jae-Young Lee, Murim Choi, Won Kim, Keon Wook Kang, Jeeyeon Lee
Clin Mol Hepatol 2026;32(1):318-338. Published online November 17, 2025
Background/Aims Ferroptosis, recently emerged as a new cell death modality characterized by iron-dependent peroxidation of lipids, has been explored in various diseases. However, detection of ferroptosis, particularly in chronic liver disease models, is hampered by the lack of universal ferroptosis markers and limited number of fluorescence sensors for in vivo ferroptosis.
Methods In this study, we developed TTM-4 as a highly sensitive near-infrared (NIR) fluorescent probe to detect ferroptosis.
Result s: TTM-4 exhibited turn-on fluorescence upon viscosity change, enabling visualization of lipid peroxidation (LPO) in ferroptotic hepatocytes and liver tissue samples with greater sensitivity than BODIPY 581/591 C11. Timelapse live-cell imaging of erastin-treated cells revealed real-time LPO dynamics involving cytosolic lipid droplets (cLDs), endoplasmic reticulum, and nuclear LDs in a chronological order. Further gene expression analysis of 216 liver tissue samples from the NCBI GEO database showed a significant increase in CIDEC concurrent with TTM-4 fluorescence during progression to metabolic dysfunction-associated steatotic hepatitis (MASH). TTM-4, with its low toxicity and turn-on NIR emission during ferroptosis, also enabled in vivo visualization of ferroptosis in liver injury and metabolic dysfunction-associated steatotic liver disease (MASLD) models.
Conclusions Our findings suggest that TTM-4 enables monitoring of ferroptosis in MASLD and would aid in early MASH diagnosis.
Chronic hepatitis B (CHB) infection remains a significant global public health concern. Functional cure, defined as hepatitis B surface antigen seroclearance with unquantifiable HBV DNA at 24 weeks off treatment, is a desirable endpoint in the treatment of CHB, yet challenging to achieve. Given the limitations of current therapies including nucleos(t)ide analogues and pegylated interferon alpha, novel agents targeting functional cure are emerging. As hepatitis B virus (HBV) is a non-cytolytic virus, liver damage stems from the host immune response towards HBV-infected cells. The innate immune response during the initial phase of HBV infection is crucial in establishing an adequate level of immunity against the virus. However, HBV adopts various mechanisms to evade the host’s innate immunity, partly contributing to the chronicity of infection. This article provides a comprehensive review on how the HBV life cycle interacts with the host’s innate immune system. The latest evidence of novel agents targeting the innate immunity will also be covered. Retinoic acid inducible gene I agonists, toll-like receptor agonists, and interferons are therapies that target the HBV evasion strategies against host’s innate immunity. While small interfering RNAs and antisense oligonucleotides are originally designed for antigen knockdown and reinvigoration of the adaptive immune response, they have also shown additional impacts on the innate immunity. With ongoing research and innovation in combination strategies, advancement in the management of CHB is anticipated in the future.
Joseph Rabbat, Boyu Yang, Hye Won Lee, Huapeng Lin, Emmanuel Tsochatzis, Salvatore Petta, Elisabetta Bugianesi, Masato Yoneda, Ming-Hua Zheng, Hannes Hagström, Jérôme Boursier, José Luis Calleja, George Boon-Bee Goh, Wah-Kheong Chan, Rocio Gallego-Durán, Arun J. Sanyal, Victor de Lédinghen, Philip N Newsome, Jian-Gao Fan, Laurent Castéra, Michelle Lai, Céline Fournier-Poizat, Grace Lai-Hung Wong, Mirko Zoncape, Grazia Pennisi, Angelo Armandi, Atsushi Nakajima, Wen-Yue Liu, Ying Shang, Marc de Saint-Loup, Elba Llop, Kevin Kim Jun Teh, Carmen Lara-Romero, Amon Asgharpour, Sara Mahgoub, Mandy Sau-Wai Chan, Clemence M Canivet, Manuel Romero-Gomez, Vincent Wai-Sun Wong, Seung Up Kim, Terry Cheuk-Fung Yip
Clin Mol Hepatol 2026;32(1):289-304. Published online November 11, 2025
Background/Aims Current guidelines recommend a 2-step approach for identifying advanced fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD), using Fibrosis-4 index (FIB-4) followed by liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE). However, some patients may exhibit discordant results. This study evaluates the histological severity and outcomes in patients with discordant FIB-4 and LSM results.
Methods This secondary analysis of the VCTE-Prognosis study included 12,950 patients evaluated for MASLD at 16 tertiary centers, of whom 2,915 underwent liver biopsy. Patients were categorized into four groups based on established FIB-4 (1.3) and LSM (8 kPa) cutoffs.
Result s: F3–F4 fibrosis was observed in 6.4%, 13.7%, 30.6%, and 62.4% in low-FIB-4-low-LSM (n=6,403), high-FIB-4-low-LSM (n=3,017), low-FIB-4-high-LSM (n=1,363), and high-FIB-4-high-LSM (n=2,167) groups, respectively. During a median follow-up of 47.4 months, 248 patients experienced hepatic decompensation, hepatocellular carcinoma, liver transplantation, or liver-related death. The incidence rates of liver-related events (LREs) were 0.67, 1.19, 2.58, and 21.30 per 1,000 person-years, respectively. Compared to low-FIB-4-low-LSM patients, those with low-FIB-4-high-LSM (adjusted subdistribution hazard ratio [aSHR] 4.12) and high-FIB-4-high-LSM (aSHR 21.38) had a significantly higher risk of LREs, while high-FIB-4-low-LSM patients did not. Similar findings were observed when hepatic decompensation and hepatocellular carcinoma were analyzed separately.
Conclusions Approximately 30% of patients in tertiary centers exhibit discordant FIB-4 and LSM results, with LSM more likely reflecting true severity. While some patients with discordant results may have advanced fibrosis, the overall incidence of LREs remains low.
Background/Aims The first metabolic dysfunction-associated steatotic liver disease (MASLD) drug was approved with an unsatisfactorily small effect size. This study aimed to determine key factors impacting the cost-effectiveness of a new hypothetical MASLD drug as well as its treatment efficacy.
Methods A Markov model reflecting the natural history of MASLD was developed, incorporating fibrosis progression, cardiovascular disease risk, and mortality. Treatment effect of drug X (with $20,000 of annual cost) was assumed to achieve a ≥1 stage fibrosis regression, with a 25% gap of effect size in regression rate over non-treatment in the first year. The incremental cost-effectiveness ratio (ICER) over a 20-year horizon was estimated. And sensitivity analyses were conducted to explore uncertainty and identify influential factors.
Result s: In the base case analysis, drug X provided an incremental gain of 1.32 quality-adjusted life years (QALYs) and 1.20 life years compared to the non-treatment, with an ICER of $68,010/QALY–below the $100,000/QALY willingnessto- pay threshold, indicating that drug X treatment is cost-effective. Two-way sensitivity analysis further highlighted that the drug should achieve at least a 15% initial regression gap and maintain a minimum 3% sustained durability gap to remain cost-effective. In addition baseline fibrosis stage distribution also acted as an influencing factor.
Conclusions Long-term sustained durability of the hypothetical drug, patient distribution based on baseline fibrosis stage, as well as initial treatment response rate are key factors that influence the cost-effectiveness of new MASLD drugs.
Jiyi Choi, Moon Gyeong Yoon, Se Ha Jang, Geum Ok Baek, Hyun Sun Jung, Na-Rae Lee, Choong Hwan Lee, Ji Eun Han, Jae Youn Cheong, Jung Woo Eun, Soon Sun Kim
Clin Mol Hepatol 2026;32(1):239-257. Published online October 27, 2025
Background/Aims Gut microbiome plays a pivotal role in metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis, yet, associated functional mechanisms and host responses of specific microbial species remain insufficiently characterized. This study investigated the Bacteroides eggerthii therapeutic effects on MASLD by integrating multi-omics analysis and experimental validation in a Western diet (WD)-induced mouse model.
Methods Candidate strains were identified using 16S rRNA gene sequencing of fecal samples from individuals with and without MASLD or obesity. B. eggerthii, a species significantly depleted in both groups, was selected for functional evaluation. Male C57BL/6J mice were fed a WD or WD supplemented with B. eggerthii (WD+B) for 12 weeks. Liver histology, serum biochemistry, fecal microbiome and metabolome profiling, and hepatic and intestinal transcriptomic analyses were performed. Anti-steatotic effects of B. eggerthii–derived metabolites were validated in vitro.
Result s: Bacteroides eggerthii supplementation significantly improved liver weight, inflammation, fibrosis, and steatosis in WD+B group compared to WD alone. PICRUSt-based LEfSe analysis revealed choloylglycine hydrolase activity enrichment in gut microbiota, and strain-specific qPCR confirmed colonization in mouse colon. Integrated transcriptomic analyses revealed lipid and bile acid signaling pathway restoration, including CD36, FXR, and FGF15. Untargeted metabolomics identified elevated 2-hydroxyisocaproic acid (HICA) as a strain-derived metabolite in feces and B. eggerthii culture supernatants. In vitro, HICA significantly reduced lipid accumulation in free fatty acid-induced steatosis models.
Conclusions Bacteroides eggerthii ameliorates MASLD via gut-liver axis modulation, including bile acid metabolism and hepatic lipid signaling. These underscore its therapeutic potential and highlight HICA as a novel microbiome-derived metabolite with anti-steatotic activity.
Eun Sun Jang, Nae Yun Heo, Jae Yoon Jeong, Jung Gil Park, Do Seon Song, Eun Ju Cho, Chang Hun Lee, Jae Seung Lee, Jae Hyun Yoon, Seul Ki Han, Young Kul Jung, on behalf of the Korean Association for the Study of the Liver (KASL)
Clin Mol Hepatol 2026;32(1):1-52. Published online October 23, 2025
Metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, has become the most common form of chronic liver disease in children. The spectrum of pediatric MASLD ranges from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and in rare cases, hepatocellular carcinoma. Its pathogenesis involves a complex interplay among genetic, epigenetic, and environmental factors, along with alterations in the gut microbiota and its associated metabolites. Given the staggering prevalence and the distinct etiopathogenesis of pediatric MASLD, characterization of the gut microbiota and microbial products could facilitate the development of diagnostic tools and inform targeted therapeutic strategies. Current research on the gut microbiome in the context of pediatric MASLD is limited by small sample size, inadequate use of liver biopsy, methodological inconsistencies in sequencing, and confounding effects from metabolic comorbidities. In this review, we summarize clinical studies on alterations in the gut microbiota and microbial products (short-chain fatty acids, bile acids, and ethanol) that impact the pathogenesis of pediatric MASLD. We discuss the therapeutic potential of dietary modification, pharmacological treatments, and probiotics in improving disease progression by summarizing current clinical studies. Enhancing our understanding of the gut-liver axis may aid in the development of effective therapeutic strategies for pediatric MASLD.
Background/Aims Excessive lipid accumulation in hepatocytes is a critical cause of metabolic dysfunction-associated steatotic liver disease (MASLD) progression. Ankyrin repeat and SOCS box protein 3 (ASB3) is an E3 ubiquitin ligase that mediates diverse disease processes; however, the direct substrates of ASB3 in lipid metabolism and its role in MASLD remain unexplored.
Methods We generated ASB3 knockout mice fed a high-fat diet to induce MASLD. Oxygen consumption and fatty acid oxidation (FAO) were used to assess lipid metabolism. LC-MS/MS and IP were used to verify the ASB3 target protein. Correlation analysis was conducted on the cohort of MASLD patients vs. the control group.
Result s: Loss of the ASB3 E3 ubiquitin ligase in hepatocytes strengthens mitochondrial FAO, thereby influencing energy consumption to decrease triglyceride storage and lipid accumulation. Quantitative lysine ubiquitination proteomics revealed that ASB3 directly mediated the ubiquitin levels at two sites (K180 and K639) in carnitine palmitoyl transferase 1A (CPT1A), a rate-limiting enzyme of FAO, to induce CPT1A degradation. Moreover, both constitutive and hepatocyte-specific ASB3 knockout enhance FAO and delay lipid accumulation, liver steatosis, and MASLD progression in a CPT1A-dependent manner. Hepatic ASB3 deficiency also delays fibrosis in MASLD. Analysis of public databases and liver tissue samples from MASLD patients revealed that ASB3 was highly expressed in MASLD patients and was negatively correlated with CPT1A.
Conclusions Our study reveals the key roles of ASB3 in the development of MASLD and suggests a novel therapeutic potential for MASLD.
Through the implementation of hepatitis B vaccination and effective antiviral treatment over the past four decades, the hepatitis B surface antigen (HBsAg) seroprevalence of the vaccinated generation dramatically decline. The incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) also decreases. However, the elimination of HBV is still a challenge to achieve. Novel HBV biomarkers, including quantitative HBsAg, hepatitis B virus core-related antigen and HBV RNA are promising in predicting clinical phases, risks of disease progression and HBV functional cure. Current antiviral therapies, nucleoside/nucleotide and pegylated alpha-interferon, effectively decrease HCC incidence in chronic hepatitis B (CHB) patients and minimize the recurrence of HCC in patients receiving curative therapy. Novel agents under development to achieve HBV cure include direct-acting antivirals that target various stages of the HBV lifecycle and host targeting agents that enhance HBV-specific immunity. The action plans for eliminating hepatitis B in the future are universal HBV screening, early and simplified treatment as well as precision lifelong management for CHB patients. This narrative review will summarize and discuss global strategies and initiatives aimed at eliminating HBV infection.
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Insight into the Biology of Hepatitis B Virus and Recent Therapeutic Approaches Prashant Tiwari, Istuti Saraswat, Jyoti Gupta Current Microbiology.2026;[Epub] CrossRef
Aspirin Use and Risk of HCC and Gastrointestinal Bleeding in Patients With HBV‐Related Cirrhosis: A Landmark Analysis Mi Na Kim, Geun U. Park, Seng Chan You, Jae Seung Lee, Hye Won Lee, Beom Kyung Kim, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn Journal of Gastroenterology and Hepatology.2025; 40(11): 2750. CrossRef
Background/Aims The role of reactivation of human cytomegalovirus (HCMV) in determining outcomes of cirrhotic patients with acute decompensation (AD) is unknown. We aimed to investigate HCMV incidence and potential correlation with hepatic outcomes in AD patients.
Methods Two prospective multicentre cohorts with AD patients were investigated. Patients in cohort 1 were recruited from 4 centres, while patients in cohort 2 were randomly selected from a second multicentre cohort. HCMV reactivation was established with quantitative real-time polymerase chain reaction assay in seropositive patients.
Result s: HCMV reactivation was found in 35 patients from cohort 1 (n=722) and 14 from cohort 2 (n=291), with an incidence of 4.8% in both cohorts. Bacterial infection and liver failure were independently correlated with HCMV reactivation. HCMV reactivation was an independent predictor of 90-day mortality. Among bacterial infection populations in these two cohorts, patients with HCMV reactivation had worse prognosis compared to those without. Incidence of acute-on-chronic liver failure (ACLF) was higher in patients with HCMV reactivation compared to those without and was also independently correlated with development of ACLF. In a total of 49 HCMV reactivation cases, 8 patients were treated with ganciclovir, in whom a significantly lower 90-day mortality compared with those not treated was observed. All 3 patients who underwent liver transplantation with reactivation of HCMV died.
Conclusions In AD patients, HCMV reactivation was common, especially in those with bacterial infection or liver failure, and they were more prone to having ACLF and 90‑day mortality. The data propose the need for active surveillance for HCMV infection in AD patients.
Background/Aims Hepatitis B virus (HBV) mother-to-child transmission (MTCT) remains a global health concern, with over 90% of perinatal infections leading to chronic HBV. To evaluate long-term trends in MTCT rates and associated factors within Korea’s national program.
Methods Population-based cohort study using linked data from the Perinatal Hepatitis B Prevention Program (PHBPP) and National Health Insurance Service in Korea. The study included HBsAg-positive mother-infant pairs with post-vaccination serologic results from 2002 to 2021.
Result s: Among the 154,478 mother-infant pairs, the overall MTCT rate after prophylaxis was 2.3%. Antiviral use lowered MTCT rates (0.9% vs. 2.4%) particularly in HBeAg-positivity (1.0% vs. 5.9%; adjusted odds ratio [aOR] 0.21; 95% confidence interval [CI] 0.14–0.32). Lower MTCT rates were observed for cesarean section vs. vaginal delivery (1.9% vs. 2.6%; aOR 0.78; 95% CI 0.73–0.84) and breastfeeding vs. formula feeding (1.8% vs. 2.8%; aOR 0.65; 95% CI 0.56–0.76). Annual MTCT rates decreased from 3.6% (2002–2005) to 1.3% (2018–2021). Antivirals reduced MTCT rates; initiation at 14–27 weeks (0.39%), or 28–32 weeks (0.44%) vs. ≥33 weeks (1.47%); postpartum continuation (0.55%) vs. antepartum discontinuation (1.44%); use ≥61 days (0.51%) vs. 1–60 days (1.67%). Lower MTCT risk was associated with maternal (old age, high income) and infant (female sex, preterm birth) factors.
Conclusions This comprehensive analysis of the PHBPP in Korea demonstrates that the use of antivirals, breastfeeding, and cesarean section, combined with conventional immunoprophylaxis, has significantly reduced MTCT rates. These results are crucial for global HBV elimination and can help to guide HBV MTCT prevention strategies.
Dong Wook Kim, Won Chang, So Yeon Kim, Young-Suk Lim, Jonggi Choi, Jungheum Cho, Jin-Wook Kim, Jai Young Cho, Sun Kyung Jeon, Yun Bin Lee, Eun Ju Cho, Su Jong Yu, Kyung-Suk Suh, Kwang-Woong Lee, Dong Ho Lee
Clin Mol Hepatol 2025;31(4):1285-1297. Published online June 13, 2025
Background/Aims Hepatocellular carcinoma (HCC) frequently recurs after curative treatment, posing challenges to long-term survival. Although contrast-enhanced multiphasic computed tomography (CECT) is commonly used for detecting recurrence, it is associated with risks such as radiation exposure and contrast agent reactions. This study aimed to compare the diagnostic performance of non-contrast magnetic resonance imaging (NC-MRI) with CECT for detecting recurrent HCC.
Methods In this prospective multicenter intra-individual head-to-head comparison trial (study identifier: NCT05690451, KCT0006395), participants who had undergone curative treatment for HCC and remained recurrence-free for over two years were enrolled. Each participant underwent three follow-up imaging sessions at 2–6-month intervals using both CECT and NC-MRI. The primary outcome was the detection accuracy of each modality, analyzed using the generalized estimating equation analysis. Secondary outcomes included sensitivity and specificity.
Result s: The study included 203 participants with a total of 528 paired imaging sessions, identifying recurrent HCC in 22 cases (10.8%). Among these, 21 cases involved intrahepatic recurrence with a median tumor size of 1.3 cm, and one case had aortocaval lymph node metastasis. NC-MRI achieved a detection accuracy of 96.6% (196/203), higher than CECT’s 91.6% (186/203) (P=0.006). NC-MRI also showed greater sensitivity (77.3% [17/22] vs. 36.4% [8/22]; P=0.012), while specificity was comparable between NC-MRI and CECT (98.9% [179/181] vs. 98.3% [178/181]; P=0.999).
Conclusions NC-MRI demonstrated higher sensitivity and accuracy compared to CECT in detecting recurrent HCC in patients who had been disease-free for over two years following curative treatment, indicating its potential as a preferred imaging modality for this purpose.
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Non-contrast magnetic resonance imaging outperforms contrast-enhanced computed tomography in preoperative detection of hepatocellular carcinoma: A paired validation study Laizhu Zhang, Weiwei Zong, Jialin Gao, Huan Li, Leizhou Xia, Xiaoli Mai, Jun Chen, Binghua Li, Decai Yu Clinical and Molecular Hepatology.2026; 32(1): e34. CrossRef
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Mendelian randomization (MR), a powerful statistical tool for causal inference, has been widely applied in various fields of medical research, even extending to economics and psychology. In hepatology, MR has been utilized to identify risk factors and potential therapeutic targets for liver diseases, including metabolic dysfunction-associated steatotic liver disease, cholestatic and autoimmune liver diseases, and hepatobiliary cancer. MR can provide evidence of causation via associations between genetic variants, modifiable exposures and liver disease occurrence or outcomes, using large existing datasets. However, results from MR studies are sometimes scattered, biologically not plausible or even controversial between analyses, potentially reflecting a trend of inappropriate application of this method (e.g., inappropriate selection of genetic instruments, insufficient assessment of horizontal pleiotropy, compromised statistical power, and neglected genetic diversity among different populations), and thus hinder the translation of MR findings from bench to bedside. Assessing these critical issues and pinpointing bona fide evidence are essential but quite challenging for clinicians. In this review, we aim to introduce the MR method to hepatologists and provide a comprehensive overview of the current MR findings that are relevant for hepatologists. Furthermore, we will discuss how to evaluate the quality of MR publications, interpret MR findings, and illustrate good practice of using MR studies in hepatology.
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Evaluating causal protective effect of dual GLP-1R/GIPR agonists on MASLD: A Mendelian randomization and colocalization study Yangke Cai, Siyuan Xie, Liyi Xu, Jiamin Chen, Jianting Cai European Journal of Pharmacology.2025; 1005: 178088. CrossRef
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Moana Witte, Carlos Oltmanns, Jan Tauwaldt, Hagen Schmaus, Jasmin Mischke, Gordon Grabert, Mara Bretthauer, Lennart M. Roesner, Thomas Werfel, Katja Deterding, Benjamin Maasoumy, Heiner Wedemeyer, Tim Kacprowski, Anke R.M. Kraft, Markus Cornberg
Clin Mol Hepatol 2025;31(4):1269-1284. Published online June 4, 2025
Background/Aims Hepatitis C virus (HCV) infection remains a global health challenge, leading to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Despite the high efficacy of direct-acting antiviral therapy in achieving sustained virologic response (SVR), concerns persist regarding long-term immune alterations and residual risks, particularly in cirrhotic patients.
Methods This study investigates 75 soluble immune mediator (SIM) profiles in 102 chronic HCV patients, stratified by cirrhosis status, at therapy initiation, end of treatment, and long-term follow-up (median 96 weeks). Findings were compared with 51 matched healthy controls and validated in an independent cohort of 47 cirrhotic patients, 17 of whom developed HCC.
Result s: We observed significant SIM alterations at baseline, with cirrhotic patients displaying a more profoundly dysregulated inflammatory milieu. Despite an overall decline in inflammatory markers following SVR, persistent alterations were evident, particularly in cirrhotic patients. Notably, those with liver stiffness exceeding 14 kPa exhibited sustained inflammatory dysregulation, correlating with liver elastography values. Key SIM such as interleukin (IL)-6, IL-8, urokinase plasminogen activator, and hepatocellular growth factor remained elevated and were associated with HCC development. Network analysis highlighted their roles in liver fibrosis, regeneration, and carcinogenesis.
Conclusions These findings underscore the importance of early antiviral intervention to prevent cirrhosis-related sequelae. Future studies should explore the mechanistic pathways linking chronic inflammation, fibrosis, and oncogenesis to identify predictive biomarkers and novel therapeutic targets. Addressing persistent immune alterations post-HCV clearance may improve long-term outcomes, particularly in patients with advanced liver disease.
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Gut microbiota–immunity cascade in hepatocellular carcinoma: mechanisms and therapeutic opportunities Jihao Yang, Yishuang Dai, Jia Li Oncology Reviews.2026;[Epub] CrossRef
HBV Dominance Is Associated With a Distinct Inflammatory Milieu in HBV/HCV Coinfection Carlos Oltmanns, Moana Witte, Anika Wranke, Katja Deterding, Heiner Wedemeyer, Christine S. Falk, Anke R. M. Kraft, Steffen B. Wiegand, Markus Cornberg Journal of Viral Hepatitis.2025;[Epub] CrossRef
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Background/Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) may progress to liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. So far, genome-wide association studies explain a small fraction of MASLD heritability.
Methods We sought to identify novel genetic determinants of MASLD by exploring interactions between genetic variants and body mass index (BMI). First, we examined genome-wide interactions with BMI for circulating alanine aminotransferase (ALT) levels using UK Biobank data. For identified loci, we next examined associations with hepatic proton density fat fraction (PDFF) in 35,146 independent UK Biobank participants. Associations with PDFF were replicated in four independent European cohorts, followed by a phenome-wide association study. Finally, we used human liver epigenomic maps and CRISPR/Cas9 experiments in vitro and in vivo to functionally characterize the CYP7A1 locus.
Result s: Thirteen loci interact with BMI for ALT (P<5E-8), including eight well-known genetic modulators of MASLD. Two loci—UBXN2B/CYP7A1 and GIPR—are additionally associated with PDFF. For the intronic rs34783010 in GIPR, the minor T allele is associated with lower BMI and higher HbA1c and liver triglyceride content in humans. The UBXN2B/CYP7A1 locus is associated with PDFF in four additional European cohorts. Epigenomic data and in vitro experiments in human liver cells prioritise rs10504255 and CYP7A1 as the functional effectors in this locus. Perturbation of CYP7A1 orthologues using CRISPR/Cas9 results in less liver fat in 10-day-old, metabolically challenged zebrafish larvae.
Conclusions A genome-wide single nucleotide polymorphism×BMI design fuelled identification of two MASLD genes: CYP7A1 and GIPR.
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Germline mutations and somatic mosaicism in steatotic liver diseases and related liver carcinogenesis Eric Trépo, Jessica Zucman-Rossi, Jean-Charles Nault Nature Reviews Gastroenterology & Hepatology.2026;[Epub] CrossRef
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Background/Aims Information about the association of glucagon-like peptide-1 receptor (GLP-1RA) with liver and non-liver complications is insufficient in patients with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). We conducted a target trial emulation study to evaluate whether GLP-1RA decreases the risk of liver and non-liver outcomes.
Methods Patients with T2D and MASLD initiating GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP-4i) were included from 2013 to 2022 in Merative™ Marketscan® Research Databases. Primary outcomes included incidences of (1) hepatocellular carcinoma (HCC) and cirrhosis, and (2) cardiovascular disease (CVD), chronic kidney disease (CKD), and non-liver cancer. Inverse probability of treatment weighting was applied to balance baseline characteristics and Cox regression models were conducted to estimate hazard ratio (HR) and 95% confidence interval (CI).
Result s: In the intention-to-treat design, GLP-1RA, compared with DPP-4i, had a significantly lower incidence (per 1,000 person-years) of HCC (0.8 vs. 1.7; HR 0.53, 95% CI 0.39–0.71), of cirrhosis (29.3 vs. 32.9; HR 0.91, 95% CI 0.86–0.96), of CVD (57.2 vs. 73.9; HR 0.90, 95% CI 0.86–0.95), of CKD (4.5 vs. 6.8; HR 0.73, 95% CI 0.64–0.84), and of non-liver cancer (16.9 vs. 22.9; HR 0.82, 95% CI 0.77–0.89). In the per-protocol design, significant inverse associations for these study outcomes still were observed, with HR 0.60–0.77.
Conclusions In this emulated target trial of nationwide patients with T2D and MASLD, GLP-1RA use, when compared with DPP-4i, was associated with a significantly lower risk of liver and non-liver complications.
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Tirzepatide versus SGLT2 inhibitors for MASLD: a multi-institutional propensity score-matched cohort study Jheng-Yan Wu, Yu-Min Lin, Wan-Hsuan Hsu, Ting-Hui Liu, Ya-Wen Tsai, Po-Yu Huang, Min-Hsiang Chuang, Tsung Yu, Chih-Cheng Lai Hepatology International.2026;[Epub] CrossRef
Evaluating causal protective effect of dual GLP-1R/GIPR agonists on MASLD: A Mendelian randomization and colocalization study Yangke Cai, Siyuan Xie, Liyi Xu, Jiamin Chen, Jianting Cai European Journal of Pharmacology.2025; 1005: 178088. CrossRef
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Background/Aims Berberine ursodeoxycholate (HTD1801) has been shown to significantly reduce liver fat content (LFC) in an 18-week, placebo-controlled Phase 2 study in patients with metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus. The purpose of this assessment was to establish proof of concept in liver histologic improvement with HTD1801 treatment based on preclinical and clinical evidence.
Methods The efficacy of HTD1801 was evaluated in a preclinical MASH/dyslipidemia model (golden hamsters fed a high fat diet, eight/group) after six weeks of daily treatment. Additionally, in a secondary analysis of a Phase 2 clinical study, 100 patients with presumed MASH were evaluated by multiple noninvasive markers associated with MASH resolution and/or fibrosis improvement. These include magnetic resonance imaging proton density fat fraction (MRIPDFF; ≥30% LFC reduction), iron-corrected T1 (≥80 ms reduction), alanine aminotransferase (≥17 U/L reduction), weight loss (≥5% reduction), Fibrosis-4 index (shift to <1.3), and MASH resolution index (achieving ≥–0.67).
Result s: Preclinical findings in the MASH/dyslipidemia hamster model showed that HTD1801 significantly improved histologic fibrosis and the Nonalcoholic Fatty Liver Disease Activity Score to such a degree that improvements approximated the appearance of the normal controls. In the clinical study, 52% of HTD1801-treated patients achieved MRI response criteria compared to 24% of placebo (p<0.05). Dose-dependent improvements were observed across biomarkers, with more HTD1801-treated patients achieving response criteria associated with improvements in the histologic features of MASH.
Conclusions These findings suggest that HTD1801 has strong potential to produce histological improvements in patients with MASH.
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Metabolic dysfunction-associated steatotic liver disease, formerly referred to as non-alcoholic fatty liver disease, is the most common liver disease in Western countries and has emerged as the leading indication for liver transplantation. Metabolic dysfunction-associated steatohepatitis (MASH), a more advanced stage, carries a high risk of progression to liver fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. Until recently, lifestyle intervention remained the mainstay of MASH management, with no pharmacological treatments specifically approved. However, advances in understanding its pathophysiological mechanisms have fueled numerous clinical trials, culminating in the Food and Drug Administration’s (FDA) approval of resmetirom as the first treatment for MASH in 2024. Additionally, many investigational drugs are nearing FDA approval or progressing through late-stage clinical trials. This review examines the current therapeutic landscape, highlights strategies for identifying patients suitable for liver-directed therapies in real-world settings, and discusses the challenges that remain.
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