Obesity and its related metabolic comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease, are increasingly recognized as heterogeneous and multisystemic disorders. Despite the significant benefits in glycemic control and weight loss exhibited by GLP-1 receptor agonists (GLP-1RAs), their limitations have initiated the development of engineered multi-agonist therapies targeting additional nutrient-stimulated hormonal (NUSH) pathways. Dual and triple peptide-based co-agonists combining glucagon-like peptide-1 (GLP-1) with glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, or peptide YY have demonstrated superior metabolic efficacy in preclinical and clinical studies. Tirzepatide (GLP-1/GIP dual agonist), CagriSema (GLP-1/amylin dual agonist), and retatrutide (GLP-1/GIP/glucagon triple agonist) have achieved unprecedented levels of weight loss and glycemic improvement, with certain agents also demonstrating hepatic, cardiovascular, and inflammatory benefits. Non-peptidyl oral GLP-1RAs, such as orforglipron, offer novel formulation strategies to enhance treatment accessibility and adherence. Multi-agonist incretin-based therapies represent a paradigm shift in the management of obesity and metabolic diseases. These agents offer broad clinical utility beyond glucose lowering by mimicking the pleiotropic hormonal responses observed after bariatric surgery. These therapies are poised to emerge as key components of precision metabolic medicine. This review article explores the mechanistic basis, pharmacological characteristics, and clinical data supporting the use of engineered NUSH-based peptide therapies for obesity and its related metabolic disorders, with particular emphasis on recent progress in the development and clinical application of dual and triple agonists.
The knowledge accumulated over the past two decades has revealed that the natural history of metabolic dysfunction-associated steatotic liver disease (MASLD) and the drivers of the disease severity are not only complex but also exhibit variation among patients. This intricate clinical scenario entails major therapeutic and management implications. In this review, we provide a comprehensive examination of recent advancements in our understanding of MASLD heterogeneity, drawing insights from multiomics and panomics studies.
The discussion herein explores the instrumental role of panomics in MASLD research, elucidating the potential for the identification of molecular subtypes that exhibit divergent survival outcomes or heterogeneous responses to various treatments. Furthermore, we provide insights into the challenges in addressing disease heterogeneity and potential solutions. Finally, the most advanced technological advancements and prospective research directions in the domain of MASLD research are delineated, with the objective of facilitating the implementation of personalized diagnosis and interventions.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formally 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.
Results 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.
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.
Citations
Citations to this article as recorded by
Helicobacter pylori, peptic ulcer disease, and colorectal cancer: a prospective study with genome-wide interaction analysis and Mendelian randomization Ziqi Wan, Jiarui Mi, Xiaoyin Bai, Dong Wu, Sunny Hei Wong Infectious Agents and Cancer.2025;[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
Integrative genome-wide analysis unveils the genetic landscape of gallstone disease and highlights novel loci with therapeutic potential Haotian Chen, Zhengye Liu, Hanze Du, Mixue Zheng, Ziqi Wan, Nan Zhao, Guanqiao Li, Xiaoyin Bai, Dong Wu, Jiarui Mi BMJ Open Gastroenterology.2025; 12(1): e001976. CrossRef
Childhood Obesity and Age‐Related Diseases: A Systematic Review and Meta‐Analysis of Mendelian Randomization Evidence Haoxue Zhu, Xinghao Yi, Mengyu He, Siyi Wu, Ming Li, Shan Gao Pediatric Obesity.2025;[Epub] CrossRef
Correspondence: Response to Editorial on “Uncovering the MET-TRIB3-FOXO1 axis: A Novel Target in MET-driven Hepatocellular Carcinoma” Tiantian Wang, Wenjie Huang, Limin Xia Clinical and Molecular Hepatology.2025;[Epub] CrossRef
Correspondence: Response to Editorial on “Unveiling TRIB3: A New Mediator in MET-Driven Hepatocellular Carcinoma Progression” Tiantian Wang, Wenjie Huang, Limin Xia Clinical and Molecular Hepatology.2025;[Epub] CrossRef
Correspondence to letter to the editor on “Risk Stratification of Metabolic Dysfunction-Associated Steatotic Liver Disease: The KASL Pathway Hye Won Lee, Seung Up Kim Clinical and Molecular Hepatology.2025;[Epub] CrossRef
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).
Results 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.
Citations
Citations to this article as recorded by
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
Impaired Thyroid Hormone Sensitivity is Associated with Increased
Risk of Liver Fibrosis in Euthyroid Population: A Cross-Sectional Analysis of
NHANES Xingyu Yao, Kaiwen Xiao, Hein Ko Oo Hormone and Metabolic Research.2025; 57(09): 511. CrossRef
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).
Results 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.
Citations
Citations to this article as recorded by
Molecular mechanisms and clinical applications of gut microbiota-derived bioactive compounds in metabolic dysfunction-associated fatty liver disease Chengyun Ma, Jing Wang, Xuanli Song, Xue Wang, Shuai Zong Frontiers in Immunology.2025;[Epub] CrossRef
Background/Aims Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and abnormal MET expression plays a crucial role in its progression. However, the specific pathogenic mechanisms of MET in HCC have yet to be fully elucidated. This study aimed to uncover the oncogenic mechanisms of MET in HCC and explore potential therapeutic implications.
Methods Transcriptomic data from the HTVi MET/β-catenin HCC model and GSEA results from TCGA LIHC cohorts were analyzed to identify key genes in HCC development. In vitro assays and in vivo models were used to investigate the role of TRIB3 in HCC progression. Immunofluorescence, co-IP, qRT-PCR, and WB revealed target genes regulated by TRIB3. An AAV8-shTRIB3 construct was developed and we assessed its therapeutic potential.
Results MET promoted HCC development both in vitro and in vivo by upregulating the oncogenic protein TRIB3. Mechanistically, MET transcriptionally activated TRIB3 via the ERK/SP1 axis. TRIB3 then recruited the E3 ubiquitin ligase COP1, which facilitated the ubiquitination and degradation of the tumor suppressor transcription factor FOXO1. TRIB3-mediated FOXO1 ubiquitination upregulated the expression of MET, CCND1 and TWIST1. In clinical HCC samples, TRIB3 expression was correlated with MET and FOXO1 levels. Liver-specific knockdown of TRIB3 by AAV8-shTRIB3 significantly inhibited MET-driven HCC development.
Conclusions Our results revealed that TRIB3 and COP1 act as key mediators in MET-driven HCC progression. Targeting the MET-TRIB3-FOXO1 regulatory axis may offer a promising therapeutic strategy to counteract oncogenic signaling and impede HCC advancement.
Citations
Citations to this article as recorded by
Bioinformatic analysis of the role of USP22 expression in hepatocellular carcinoma Kemin Xu International Journal of Clinical and Experimental Pathology.2025; 18(7): 287. CrossRef
Mapping the current research landscape of metformin in cancer based on bibliometric analysis Yuan Wang, Sike He, Ziqi Li, Nan Jiang, Guangxi Sun Discover Oncology.2025;[Epub] CrossRef
Correspondence: Response to Editorial on “Unveiling TRIB3: A New Mediator in MET-Driven Hepatocellular Carcinoma Progression” Tiantian Wang, Wenjie Huang, Limin Xia Clinical and Molecular Hepatology.2025;[Epub] CrossRef
FOXO1-mediated argininosuccinate lyase transcription inhibits ammonia metabolism and breast cancer cell metastasis Min Zhao, Dongdong Yuan, Mengmeng Wei, Jie Zhang, Wenjing Yang, Shaojie Qin, Le Li Journal of Biological Chemistry.2025; 301(10): 110677. CrossRef
Background/Aims Recently, the Korean Association for the Study of the Liver (KASL) introduced a noninvasive test-based approach that uses the fibrosis-4 (FIB-4) index followed by vibration-controlled transient elastography (VCTE) to identify high-risk patients with metabolic-associated steatotic liver disease (MASLD). In this study, the KASL two-step approach was validated by assessing the risk of liver-related event (LRE) development.
Methods We retrospectively analyzed 8,131 patients with MASLD who underwent VCTE between 2012 and 2020. The index date was defined as the date of the VCTE measurement. Using the KASL two-step approach (FIB-4 index and subsequent VCTE), patients were stratified into four groups (low-, intermediate-low-, intermediate-high-, and high-risk groups). Outcomes, including LREs such as decompensation (DCC) or hepatocellular carcinoma (HCC) were evaluated.
Results During the follow-up (median 46.6 months), 86 (1.1%) patients developed LREs (39 [0.5%] with DCC and 47 [0.6%] with HCC). The KASL two-step approach classified 67.6%, 17.7%, 5.7% and 9.0% of patients in the low-, intermediate-low-, intermediate-high-, and high-risk groups, respectively. The cumulative incidences of LREs increased proportionally according to risk stratification (0.07%, 0.10%, 0.29%, and 1.51% at 3 years and 0.35%, 0.26%, 1.94% and 5.46% at 5 years). The overall accuracy in predicting LREs ranged from 67.7–99.8%. The FIB-4 index and subsequent Agile3+, Agile 4, or FibroScan aspartate aminotransferase scores showed similar predictive abilities compared to the KASL approach.
Conclusions The KASL two-step approach is an effective and practical method for risk stratification in patients with MASLD, optimizing patient care through early identification of high-risk individuals.
Citations
Citations to this article as recorded by
Validation of combo ichroma as a reliable concentration-based alternative for AST and ALT measurement in liver disease monitoring Minsoo Kim, Su A Kim, Jeong Min Kim, Hee Young Kim, Ho Yeong Yoon, Sung Won Park, Daegyun Park, Ji Sook Han, Ki Tae Suk Methods.2025; 243: 66. CrossRef
Correspondence to letter to the editor on “Risk Stratification of Metabolic Dysfunction-Associated Steatotic Liver Disease: The KASL Pathway Hye Won Lee, Seung Up Kim Clinical and Molecular Hepatology.2025;[Epub] CrossRef
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.
Citations
Citations to this article as recorded by
Steatotic Liver Disease in Older Adults: Clinical Implications and Unmet Needs Daniel Clayton-Chubb, William W. Kemp, Ammar Majeed, Peter W. Lange, Jessica A. Fitzpatrick, Karl Vaz, John S. Lubel, Alexander D. Hodge, Joanne Ryan, John J. McNeil, Alice J. Owen, Robyn L. Woods, Stuart K. Roberts Nutrients.2025; 17(13): 2189. CrossRef
Tirzepatide in metabolic dysfunction-associated steatotic liver disease and steatohepatitis: a novel star on the horizon? Amedeo Lonardo, Ralf Weiskirchen Exploration of Drug Science.2025;[Epub] CrossRef
Timosaponin AIII from Anemarrhena asphodeloides binds and inhibits S100A8-mediated neutrophil infiltration and NET formation ameliorates MASH Yunfan Bai, Jingxin Ju, Ruishi Xie, Jing Li, Xinyi Zhao, Xiaoxue Fang, Ming Zhu, Xintian Lan, Haoming Luo International Immunopharmacology.2025; 166: 115539. CrossRef
Full Active Nanoplatform Restores ROS Homeostasis for Synergistic Therapy of Fatty Liver Disease via Dual Endogenous–Exogenous Pathways Ziyi Lin, Peng Xu, Yuehai Xu, Yixin Zheng, Huimin Li, Zixin Chen, Zhe Wang, Shaochen Song, Yuhao Liu, Zhao Yang, Ju Cui, Heyun Shen ACS Applied Materials & Interfaces.2025;[Epub] CrossRef
Quzhou-sourced Fructus Aurantii ameliorates MASLD by modulating glycolysis-dependent M1 polarization in hepatic macrophages Junbin Yan, Yunmeng Nie, Menglu Ding, Mi Zhou, Tingyuan Li, Sumei Xu, Shuo Zhang Phytomedicine.2025; : 157572. CrossRef
From mechanisms to management: Early detection and improved treatment of MASLD and its related hepatocellular carcinoma Dingwu Li, Xiang Zhang Hepatology Communications.2025;[Epub] CrossRef
Background/Aims Given the increase in prevalence of metabolic diseases, we investigated their long-term impacts on the outcomes of chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA) treatment.
Methods We analyzed data from CHB patients for whom initiated NA treatment from 30 centers. We balanced patient characteristics with and without metabolic disease (diabetes, obesity, dyslipidemia, and hypertension) via propensity-score matching (PSM) to evaluate adverse outcomes.
Results The study included 4,500 patients. PSM yielded 909 pairs of patients with balanced characteristics. When stratified by the number of metabolic diseases, only patients with ≥2 metabolic diseases had an increased cumulative incidence of cirrhosis and overall death. However, when stratified by the presence of diabetes (regardless of the presence or number of other metabolic diseases), patients with diabetes (versus those without) had a significantly higher cumulative incidence of all outcomes: cirrhosis (P=0.009), hepatocellular carcinoma (HCC, P=0.023), and overall, liver-related, and non-liver-related death (P<0.001, P=0.026 and P<0.001, respectively). Having ≥2 metabolic diseases was associated with cirrhosis, overall death, and non-liver-related death but not HCC or liver-related death, while diabetes was significantly associated with a higher risk of all outcomes: cirrhosis (hazard ratio [HR]=3.75, P=0.004), HCC (HR=2.02, P=0.020), and overall, liver-related, and non-liver-related death (HR=2.53, P<0.001; HR=2.65, P=0.016; HR=2.38, P<0.001).
Conclusions Having two or more metabolic diseases was associated with a higher risk of cirrhosis, overall death, and non-liver-related death, but having diabetes as a single metabolic disease was significantly associated with all adverse outcomes including cirrhosis, HCC, and overall, liver-related, and non-liver-related death.
Citations
Citations to this article as recorded by
Differential HCC risk among HBV indeterminate types at baseline and by phase transition Rui Huang, Huy N Trinh, Satoshi Yasuda, Angela Chau, Mayumi Maeda, Ai-Thien Do, Daniel Q Huang, Takanori Ito, Takashi Honda, Masatoshi Ishigami, Ritsuzo Kozuka, Carmen Monica Preda, Cheng-Hao Tseng, Sebastián Marciano, Pei-Chien Tsai, Dong Hyun Lee, Chris Gut.2025; 74(11): 1873. CrossRef
Type 2 diabetes mellitus as an independent predictor of significant fibrosis in treatment-naïve chronic hepatitis B patients with concurrent hepatic steatosis Jie Li, Liang Xu, Fajuan Rui, Sally Tran, Pei-Chien Tsai, Youwen Tan, Hidenori Toyoda, Qing-Lei Zeng, Huy Trinh, Yao-Chun Hsu, Tsunamasa Watanabe, Hiroshi Abe, Hiroyuki Motoyama, Yoko Yoshimaru, Takanori Suzuki, Taeang Arai, Masanori Atsukawa, Phillip Vut Hepatology.2025;[Epub] CrossRef
Incidence and determinants of achieving HBsAg <100 IU/mL in HBeAg-negative CHB patients with nucleos(t)ide analogue treatment Jian Wang, Tao Fan, Zhiyi Zhang, Li Zhu, Shaoqiu Zhang, Ye Xiong, Chun Shan, Chao Jiang, Shengxia Yin, Xin Tong, Renling Yao, Juan Xia, Xiaomin Yan, Yu Shi, Yuxin Chen, Xingxiang Liu, Huali Wang, Haixia Zhang, Chuanwu Zhu, Qun Zhang, Chao Wu, Rui Huang Emerging Microbes & Infections.2025;[Epub] CrossRef
Impact of metabolic dysfunction on treatment responses to nucleos(t)ide analogues in chronic hepatitis B: a retrospective multi-center REAL-B cohort study Rui Huang, Dae Won Jun, Hidenori Toyoda, Yao-Chun Hsu, Huy Trinh, Akito Nozaki, Toru Ishikawa, Tsunamasa Watanabe, Haruki Uojima, Daniel Q. Huang, Takashi Honda, Yasuhito Tanaka, Philip Vutien, Sebastián Marciano, Hiroshi Abe, Masaru Enomoto, Masanori Ats eClinicalMedicine.2025; 87: 103407. 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
Establishment and evaluation of an immortalized dzo kidney cell line Wenkai Liu, Cong Xu, Jiamin Wang, Na Sun, Zhongren Ma, Jin Zhao, Jianguo Chen, You Li, Zilin Qiao Scientific Reports.2025;[Epub] CrossRef
Background/Aims Previously, we advocated the importance of classifying hepatocellular carcinoma (HCC) based on physiological functions. This study aims to classify HCC by focusing on liver-intrinsic metabolism and glycolytic pathway in cancer cells.
Methods Comprehensive RNA/DNA sequencing, immunohistochemistry, and radiological evaluations were performed on HCC tissues from the training cohort (n=136) and validated in 916 public samples. HCC was classified using hierarchical clustering and compared with previous molecular, histopathological, and hemodynamic classifications.
Results Liver-specific metabolism and glycolysis are mutually exclusive and were divided into two major subclasses: The “rich metabolism” subclass (60.3%) is characterized by enhanced bile acid and fatty acid metabolism, wellto-moderate differentiation, microtrabecular or pseudoglandular pattern, and homogeneous arterial-phase hyperenhancement (APHE), corresponding to Hoshida S3 with favorable prognosis. In IL6-JAK-STAT3-high (25.0%) conditions, upregulated ALB expression, enhanced gluconeogenesis and urea cycle activity, and an inflammatorymicroenvironment are observed. Conversely, the Wnt/β-catenin-high environment (19.9%) features elevated GLUL, APOB and CYP3A4 expression, frequent CTNNB1 (D32–S37) mutations, and an immune-desert/excluded phenotype. The “glycolysis” subclass (39.7%), characterized by histopathological dedifferentiation and downregulated liver-specific metabolism, encompasses subclasses with PI3K/mTOR (20.6%) and NOTCH/TGF-β (19.1%) signaling. These often exhibit TP53 mutations, macrotrabecular massive or compact patterns, inhomogeneous/rim-APHE, and high expression of hypoxia-inducible factors and glucose transporters, corresponding to Hoshida S1/2 with poor prognosis.
Conclusions The loss of liver-specific metabolism correlates with morphological dedifferentiation, indicating cellular dedifferentiation may exhibit both physiological and pathological duality. Key signaling pathways involved in the maturation process from fetal to adult liver and zonation program may play a critical role in defining HCC diversity.
Citations
Citations to this article as recorded by
Correspondence to editorial on “Molecular Classification of Hepatocellular Carcinoma based on Zoned Metabolic Feature and Oncogenic Signaling Pathway.” Tomoko Aoki, Naoshi Nishida, Masatoshi Kudo Clinical and Molecular Hepatology.2025;[Epub] CrossRef
Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography: A Potential Imaging Biomarker for Predicting Response to Combination Immunotherapy in Hepatocellular Carcinoma Masatoshi Kudo Liver Cancer.2025; 14(5): 511. CrossRef
Won Sohn, Young-Sun Lee, Soon Sun Kim, Jung Hee Kim, Young-Joo Jin, Gi-Ae Kim, Pil Soo Sung, Jeong-Ju Yoo, Young Chang, Eun Joo Lee, Hye Won Lee, Miyoung Choi, Su Jong Yu, Young Kul Jung, Byoung Kuk Jang, on behalf of The Korean Association for the Study of the Liver (KASL)
Clin Mol Hepatol 2025;31(Suppl):S1-S31. Published online February 19, 2025
Differential Infiltration of T-Cell Populations in Tumor and Liver Tissues Predicts Recurrence-Free Survival in Surgically Resected Hepatocellular Carcinoma Eun Ji Jang, Ho Joong Choi, Young Kyoung You, Deok Hwa Seo, Mi Hyun Kwon, Keungmo Yang, Jaejun Lee, Jeong Won Jang, Seung Kew Yoon, Ji Won Han, Pil Soo Sung Cancers.2025; 17(9): 1548. CrossRef
Metabolic Dysfunction-Associated Steatotic Liver Disease, Recent Revision of Terminology and Its Implications Hyo Young Lee, Eileen L. Yoon The Korean Journal of Gastroenterology.2025; 85(2): 126. CrossRef
Advances in identifying risk factors of metabolic dysfunction-associated alcohol-related liver disease Rui-Qi Ye, Yi-Fan Chen, Chang Ma, Xi Cheng, Wei Guo, Sha Li Biomedicine & Pharmacotherapy.2025; 188: 118191. CrossRef
A Case Report of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) with Improved Cardiometabolic Risk Factors Following Treatment with Saenggangunbi-tang Eun Kyung Lee, Min Jeong Park, Youngchul Kim, Jang-Hoon Lee The Journal of Internal Korean Medicine.2025; 46(2): 303. CrossRef
Food Nutrients and Bioactive Compounds for Managing Metabolic Dysfunction-Associated Steatotic Liver Disease: A Comprehensive Review Erdenetsogt Dungubat, Kohei Fujikura, Masahiko Kuroda, Toshio Fukusato, Yoshihisa Takahashi Nutrients.2025; 17(13): 2211. CrossRef
Associations between steatotic liver disease subtypes and incident atrial fibrillation in young adults: a nationwide cohort study Jeayeon Park, Goh Eun Chung, Su Jong Yu, Yoon Jun Kim, Jung-Hwan Yoon, Kyungdo Han, Eun Ju Cho Cardiovascular Diabetology.2025;[Epub] CrossRef
Second-line antidiabetic drugs: friend or foe of the liver Jiwon Yang, Gunho Kim, Ju Hyun Shim, Jihyun An Journal of Liver Cancer.2025; 25(2): 187. CrossRef
Extrahepatic manifestation of metabolic dysfunction-associated steatotic liver disease Anoushka Shenoy, Aijaz Ahmed, Donghee Kim Metabolism and Target Organ Damage.2025;[Epub] CrossRef
2025 Clinical Practice Guidelines for Diabetes: Management of Metabolic Dysfunction-Associated Steatotic Liver Disease Jaehyun Bae The Journal of Korean Diabetes.2025; 26(3): 172. CrossRef
Paired snRNA-seq and scRNA-seq analysis of MASLD patients to identify early-stage markers for disease progression Suebin Park, Su-Hyeon Lee, Se-eun Han, Beom Kyung Kim, Byungjin Hwang Hepatology Communications.2025;[Epub] CrossRef
Sex Hormones and Metabolic Dysfunction-Associated Steatotic Liver Disease Ralf Weiskirchen, Amedeo Lonardo International Journal of Molecular Sciences.2025; 26(19): 9594. CrossRef
Discovery of ultrasound-derived fat fraction as a non-invasive tool for MASLD diagnosis Huiru Jin, Mengfan Jiao, Chengxiao Yu, Tingting Ren, Qingling Chen, Zixing Dai, Erfu Xie, Longfeng Jiang, Yuwen Li European Journal of Medical Research.2025;[Epub] CrossRef
Risk of Esophageal and Gastric Cancer by Histologic Subtype in Steatotic Liver Disease: A UK Biobank Study Donghoon Kang, Ji Won Han, Kenneth R. Muir, Artitaya Lophatananon, Jongin Lee Cancers.2025; 17(21): 3416. CrossRef
Probiotic-Derived Strain-Specific Metabolites Ameliorate Metabolic Dysfunction–Associated Steatotic Liver Disease through Modulation of the Gut-Liver Axis Sang Jun Yoon, Jieun Choi, Sung-Min Won, Jeong Seok Yu, Hee Young Kim, Hyun Chae Joung, In Gyu Park, Jung A Eom, Sang Hak Han, Do Yup Lee, Ki Tae Suk Probiotics and Antimicrobial Proteins.2025;[Epub] CrossRef
From liver to gut: the hidden gastrointestinal impact of pediatric metabolic dysfunction-associated steatotic liver disease Gianmario Forcina, Vittoria Frattolillo, Maria De Cesare, Assunta Floriano, Rosamaria Palma, Federica Casamassima, Mario Bartiromo, Pierluigi Marzuillo, Emanuele Miraglia del Giudice, Anna Di Sessa Expert Review of Gastroenterology & Hepatology.2025; : 1. CrossRef
Hyung Seok Kim, Jung Hwan Yoon, Ji Yi Choi, Moon Gyeong Yoon, Geum Ok Baek, Minji Kang, Se Ha Jang, Won Park, Yunjin Go, Jestlin Tianthing Ng, Suk Woo Nam, Jee-Yeong Jeong, Ji Eun Han, Hyo Jung Cho, Su Bin Lim, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun
Clin Mol Hepatol 2025;31(3):914-934. Published online February 6, 2025
Background/Aims Hepatocellular carcinoma (HCC) is characterized by high recurrence and mortality, necessitating the identification of reliable biomarkers. In this study, we aimed to identify the predictive gene signatures for HCC recurrence and evaluate the efficiency of GULP PTB domain-containing engulfment adaptor 1 (GULP1) as a predictive and diagnostic marker and therapeutic target for HCC.
Methods We analyzed genomic datasets from The Cancer Genome Atlas and Gene Expression Omnibus databases via least absolute shrinkage and selection operator Cox regression and 10-fold cross-validation, leading to the development of a 15-gene risk score model, which was validated using three independent datasets. Serum GULP1 and α-fetoprotein levels were assessed to determine the diagnostic accuracy of the model. Using clinical cohorts and patient sera, GULP1 roles were examined, and functional assays in vitro and in vivo were used to evaluate its effects on cell growth, epithelial–mesenchymal transition (EMT), ADP-ribosylation factor 6 (ARF6) activation, and β-catenin signaling.
Results Our newly developed risk-score model accurately predicted recurrent HCC in all datasets. Among the 15 genes in the risk score model, GULP1 was overexpressed in patients with HCC and independently predicted HCC recurrence. Its expression modulation influenced cell growth and EMT, with observed effects on ARF6 activation and β-catenin signaling pathways.
Conclusions GULP1 is a crucial biomarker for HCC, serving as a non-invasive diagnostic and predictive tool. It also plays key roles in HCC progression. Our findings highlight the potential use of GULP1 in treatment strategies targeting EMT and HCC recurrence to improve the personalized care and patient outcomes.
Citations
Citations to this article as recorded by
The evolving landscape of biomarkers for systemic therapy in advanced hepatocellular carcinoma Xinyu Guo, Zhongwei Zhao, Lingyi Zhu, Shuang Liu, Lingling Zhou, Fazong Wu, Shiji Fang, Minjiang Chen, Liyun Zheng, Jiansong Ji Biomarker Research.2025;[Epub] CrossRef
Advances in research regarding epithelial-mesenchymal transition and prostate cancer Xi Wei, Rui Liu, Wei Li, Qi Yu, Qing Tao Yang, Tao Li Frontiers in Cell and Developmental Biology.2025;[Epub] CrossRef
Correspondence: Response to the Letter Regarding "GULP1 as a Novel Diagnostic and Predictive Biomarker in Hepatocellular Carcinoma" Hyung Seok Kim, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun Clinical and Molecular Hepatology.2025;[Epub] CrossRef
Serum Proteomic Profile Based on the TGF‐β Pathway Stratifies Risk of Hepatocellular Carcinoma Xiyan Xiang, Kirti Shetty, Herbert Yu, Bibhuti Mishra, Linda L. Wong, Xianghong Jasmine Zhou, Sanjaya K. Satapathy, James M. Crawford, Patricia S. Latham, Steven‐Huy Han, Brandon Mathew, Nabil N. Dagher, Lawrence Lau, Fellanza Cacaj, Anil K. Vegesna, Srin Liver International.2025;[Epub] CrossRef
Systematic analysis of the expression profiles and prognostic values of the FAM72 family in liver cancer Weihao Kong, Long Teng, Kangjie Zhang, Yajun Zou, Xingyu Wang, Jianlin Zhang Biochemistry and Biophysics Reports.2025; 44: 102358. CrossRef
Background/Aims Hepatitis B virus (HBV) hijacks host cell metabolism, especially host glutamine metabolism, to support its replication. Glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme crucial for glutamine metabolism, can interact with histone demethylases to regulate gene expression through histone methylation. However, the mechanisms underlying GDH1-mediated glutamine metabolism reprogramming and the roles of key metabolites during HBV infection remain unclear.
Methods Transcriptomic and metabolomic analyses of HBV-infected cell were performed. Both HBV-infected cells and humanized liver chimeric mice were used to elucidate the effect of glutamine metabolism on HBV.
Results HBV infection leads to the abnormal activation of glutamine metabolism, including upregulation of key enzymes and metabolites involved in glutamine metabolism. The viral core protein (HBc) mediates the translocation of GDH1 into the nucleus, where GDH1 activates covalently closed circular DNA (cccDNA) transcription by converting glutamate to α-ketoglutarate (αKG). Mechanistically, the promoting effect of GDH1-derived αKG on cccDNA transcription is independent of its conventional role. Rather, αKG directly interacts with the lysine-specific demethylase KDM4A and enhances KDM4A demethylase activity to regulate αKG-dependent histone demethylation, controlling cccDNA transcription.
Conclusions Our findings highlight the importance of glutamine metabolism in HBV transcription and suggest that glutamine deprivation is a potential strategy for silencing cccDNA transcription.
Citations
Citations to this article as recorded by
The roles of sugar metabolism mechanisms and metabolites in viral infections Jieyi He, Xianghong Ju, A.M. Abd El-Aty, Xiaoxi Liu, Xiaowen Li Virology.2026; 615: 110764. CrossRef
HBV and host metabolic crosstalk: Reprogramming pathways for viral replication and pathogenesis YanYing Yan, Zhiqiang Wei, Min Zheng, Mengji Lu, Xueyu Wang Virologica Sinica.2025; 40(5): 685. CrossRef
GOLM1 and bile acid synthesis: Correspondence to editorial on “GOLM1 promotes cholesterol gallstone formation via ABCG5-mediated cholesterol efflux in MASH livers” Yi-Tong Li, Wei-Qing Shao, Zhen-Mei Chen, Jing Lin, Jin-Hong Chen Clinical and Molecular Hepatology.2025; 31(2): e189. CrossRef
Reply to correspondence 2 on “GOLM1 promotes cholesterol gallstone formation via ABCG5-mediated cholesterol efflux in MASH livers” Nahee Hwang, Sungsoon Fang Clinical and Molecular Hepatology.2025; 31(2): e228. CrossRef
Hyaluronic Acid Hydrogel Implants for Sustained Release of Oxaliplatin and Resiquimod to Prevent Hepatocellular Carcinoma Recurrence Post‐Radiofrequency Ablation Yuezhan Shan, Hongyu Chu, Sheyu Ye, Guofeng Ji, Jiayi Zhao, Xinghui Si, Yumin Zhong, Youmao Tao, Jingwei Shi, Xuedong Fang Advanced Science.2025;[Epub] CrossRef
A demethylation chloroisosulochrin and a chromone metabolite from the endophytic fungus
Penicilium
sp.
Ke-Liang Chen, Xue Wang, Yang Liu, Yun-Bao Liu Journal of Asian Natural Products Research.2025; : 1. CrossRef
Reply to correspondence 1 on “GOLM1 promotes cholesterol gallstone formation via ABCG5-mediated cholesterol efflux in MASH livers” Yoon-su Ha, Won Kim, Seung-Jin Kim Clinical and Molecular Hepatology.2025; 31(2): e226. CrossRef
Reply to correspondence 1 on “GOLM1 promotes cholesterol gallstone formation via ABCG5-mediated cholesterol efflux in MASH livers” Yoon-su Ha, Won Kim, Seung-Jin Kim Clinical and Molecular Hepatology.2025; 31(2): e226. CrossRef
Correspondence to editorial on “GOLM1 promotes cholesterol gallstone formation via ABCG5-mediated cholesterol efflux in MASH livers” Yi-Tong Li, Wei-Qing Shao, Zhen-Mei Chen, Jing Lin, Jin-Hong Chen Clinical and Molecular Hepatology.2025; 31(2): e186. CrossRef
Background/Aims Hepatocellular carcinoma (HCC) exhibits high de novo recurrence rates post-resection. Current post-surgery recurrence prediction methods are limited, emphasizing the need for reliable biomarkers to assess recurrence risk. We aimed to develop methylation-based markers for classifying HCC patients and predicting their risk of de novo recurrence post-surgery.
Methods In this retrospective cohort study, we analyzed data from HCC patients who underwent surgical resection in Korea, excluding those with recurrence within one year post-surgery. Using the Infinium Methylation EPIC array on 140 samples in the discovery cohort, we classified patients into low- and high-risk groups based on methylation profiles. Distinctive markers were identified through random forest analysis. These markers were validated in the cancer genome atlas (n=217), Validation cohort 1 (n=63) and experimental Validation using a methylation-sensitive high-resolution melting (MS-HRM) assay in Validation cohort 1 and Validation cohort 2 (n=63).
Results The low-risk recurrence group (methylation group 1; MG1) showed a methylation average of 0.73 (95% confidence interval [CI] 0.69–0.77) with a 23.5% recurrence rate, while the high-risk group (MG2) had an average of 0.17 (95% CI 0.14–0.20) with a 44.1% recurrence rate (P<0.03). Validation confirmed the applicability of methylation markers across diverse populations, showing high accuracy in predicting the probability of HCC recurrence risk (area under the curve 96.8%). The MS-HRM assay confirmed its effectiveness in predicting de novo recurrence with 95.5% sensitivity, 89.7% specificity, and 92.2% accuracy.
Conclusions Methylation markers effectively classified HCC patients by de novo recurrence risk, enhancing prediction accuracy and potentially offering personalized management strategies.
First
Prev
