Pub Date : 2026-01-12DOI: 10.1097/hep.0000000000001672
Yawen Dong, Hannah E. Stumpf, Rory L. Smoot, Patrick P. Starlinger, Mark M. Yarchoan, Gregory J. Gores, Sumera I. Ilyas
Cholangiocarcinoma (CCA) represents a biologically and clinically heterogeneous group of biliary tract malignancies. Growing evidence underscores that the three major anatomic subtypes – intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) – are distinct tumor entities rather than a single disease. Each subtype differs in embryologic origin, carcinogenesis mechanisms, molecular landscape, and immunogenic profile, all of which contribute to variability in diagnosis, treatment responsiveness and prognosis. The importance of understanding these distinctions is reinforced by the rising global incidence of CCA, highlighting precision medicine approaches based on these subtypes. Recent advances have deepened our insight into subtype-specific risk factors, including chronic biliary diseases and metabolic conditions, while artificial intelligence–driven tools are improving diagnostic accuracy and risk stratification. Surgical innovations now allow for more tailored resections and perioperative care, and therapeutic strategies are increasingly guided by molecular and immune profiling. Emerging strategies for early diagnosis and chemoprevention in high-risk populations further emphasize the significance of recognizing the unique biology of each subtype. In this review, we provide a comprehensive overview of the distinct anatomic subsets of CCA, integrating their molecular and biological foundations with clinical management to inform practice and guide future research.
{"title":"Anatomic subsets of cholangiocarcinoma: More different than alike","authors":"Yawen Dong, Hannah E. Stumpf, Rory L. Smoot, Patrick P. Starlinger, Mark M. Yarchoan, Gregory J. Gores, Sumera I. Ilyas","doi":"10.1097/hep.0000000000001672","DOIUrl":"https://doi.org/10.1097/hep.0000000000001672","url":null,"abstract":"Cholangiocarcinoma (CCA) represents a biologically and clinically heterogeneous group of biliary tract malignancies. Growing evidence underscores that the three major anatomic subtypes – intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) – are distinct tumor entities rather than a single disease. Each subtype differs in embryologic origin, carcinogenesis mechanisms, molecular landscape, and immunogenic profile, all of which contribute to variability in diagnosis, treatment responsiveness and prognosis. The importance of understanding these distinctions is reinforced by the rising global incidence of CCA, highlighting precision medicine approaches based on these subtypes. Recent advances have deepened our insight into subtype-specific risk factors, including chronic biliary diseases and metabolic conditions, while artificial intelligence–driven tools are improving diagnostic accuracy and risk stratification. Surgical innovations now allow for more tailored resections and perioperative care, and therapeutic strategies are increasingly guided by molecular and immune profiling. Emerging strategies for early diagnosis and chemoprevention in high-risk populations further emphasize the significance of recognizing the unique biology of each subtype. In this review, we provide a comprehensive overview of the distinct anatomic subsets of CCA, integrating their molecular and biological foundations with clinical management to inform practice and guide future research.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"24 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1097/hep.0000000000001670
Cyriac Abby Philips, Tharun Tom Oommen, Rizwan Ahamed
{"title":"Letter to the Editor: Placebo drift, dose heterogeneity and the winner’s curse – re-evaluating the hierarchy of MASH therapeutics","authors":"Cyriac Abby Philips, Tharun Tom Oommen, Rizwan Ahamed","doi":"10.1097/hep.0000000000001670","DOIUrl":"https://doi.org/10.1097/hep.0000000000001670","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"15 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background & Aims: Accurate N-staging of intrahepatic cholangiocarcinoma (iCCA) remains challenging using noninvasive approaches. We aimed to develop a model to refine lymph node (LN) involvement stratification and inform therapeutic consideration. Approach and Results: This study enrolled a discovery cohort (n=682), an internal test cohort from the FU-iCCA (n=204) and an external multicenter cohort (n=88) for model development, and a neoadjuvant therapy (NAT) cohort (n=145) for therapeutic evaluation of the model. A SwinU-CliRad framework was constructed by integrating Swin UNEt TRansformers (SwinU)–based magnetic resonance imaging-derived outputs of LN involvement with clinicoradiological features. Correlations between SwinU outputs and tumor multi-omics profiles were explored. The SwinU-CliRad model achieved area under the curves of 0.932, 0.867, and 0.888 in LN risk stratification, and outperformed radiologist-based assessments by correcting more misclassifications than it introduced across the discovery, internal and external test cohorts (18.8% vs. 7.3%, 18.1% vs. 4.9%, and 17.0% vs. 5.7%), respectively. In the NAT cohort, patients classified as high LN-involved risk by the SwinU-CliRad exhibited lower residual viable tumor rates than those with low LN-involved risk, with higher rates of pathological complete response (12.0% vs. 4.2%) and major pathological response (14.0% vs. 8.4%). SwinU outputs were associated with KRAS mutations, MUC5AC overexpression and the large-duct histological subtype. Single-cell RNA sequencing analysis linked LN involvement to an immune-suppressive stroma tumor microenvironment. Conclusion: The SwinU-CliRad model can serve as a biologically interpretable tool for LN risk stratification in iCCA surgical candidates, with high-risk patients identified by the model potentially deriving benefit from NAT.
{"title":"Biologically interpretable deep learning–derived MRI phenotypes reveal lymph node involvement and neoadjuvant therapy response in intrahepatic cholangiocarcinoma","authors":"Wentao Wang, Siqi Yin, Qianhui Xu, Danjun Song, Danlan Lian, Jinjun Wang, Xiangge Guo, Danjiang Huang, Jiayi Xing, Lei Wu, Xuping Mao, Wei Sun, Ruoyu Shi, Qiang Gao, Kai Zhu, Manning Wang, Dong Liangqing, Sheng-xiang Rao","doi":"10.1097/hep.0000000000001671","DOIUrl":"https://doi.org/10.1097/hep.0000000000001671","url":null,"abstract":"Background & Aims: Accurate N-staging of intrahepatic cholangiocarcinoma (iCCA) remains challenging using noninvasive approaches. We aimed to develop a model to refine lymph node (LN) involvement stratification and inform therapeutic consideration. Approach and Results: This study enrolled a discovery cohort (n=682), an internal test cohort from the FU-iCCA (n=204) and an external multicenter cohort (n=88) for model development, and a neoadjuvant therapy (NAT) cohort (n=145) for therapeutic evaluation of the model. A SwinU-CliRad framework was constructed by integrating Swin UNEt TRansformers (SwinU)–based magnetic resonance imaging-derived outputs of LN involvement with clinicoradiological features. Correlations between SwinU outputs and tumor multi-omics profiles were explored. The SwinU-CliRad model achieved area under the curves of 0.932, 0.867, and 0.888 in LN risk stratification, and outperformed radiologist-based assessments by correcting more misclassifications than it introduced across the discovery, internal and external test cohorts (18.8% vs. 7.3%, 18.1% vs. 4.9%, and 17.0% vs. 5.7%), respectively. In the NAT cohort, patients classified as high LN-involved risk by the SwinU-CliRad exhibited lower residual viable tumor rates than those with low LN-involved risk, with higher rates of pathological complete response (12.0% vs. 4.2%) and major pathological response (14.0% vs. 8.4%). SwinU outputs were associated with <jats:italic toggle=\"yes\">KRAS</jats:italic> mutations, <jats:italic toggle=\"yes\">MUC5AC</jats:italic> overexpression and the large-duct histological subtype. Single-cell RNA sequencing analysis linked LN involvement to an immune-suppressive stroma tumor microenvironment. Conclusion: The SwinU-CliRad model can serve as a biologically interpretable tool for LN risk stratification in iCCA surgical candidates, with high-risk patients identified by the model potentially deriving benefit from NAT.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"29 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1097/hep.0000000000001674
Tin Bo Nicholas Lam, Nidhi P. Goyal, Kimberly P. Newton, Jeffrey B. Schwimmer
{"title":"Reply: The PNPLA3 paradox: Does genotype modify the clinical utility of the MASLD framework in children?","authors":"Tin Bo Nicholas Lam, Nidhi P. Goyal, Kimberly P. Newton, Jeffrey B. Schwimmer","doi":"10.1097/hep.0000000000001674","DOIUrl":"https://doi.org/10.1097/hep.0000000000001674","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"14 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1097/hep.0000000000001675
Vanilla Xin Zhang, Tina Suoangbaji, Yu‑Man Tsui, Karen Man-Fong Sze, Eva Lee, Lu Tian, Jingyi Lu, Huan Deng, Abdullah Husain, Charry Shuk-Ching Hui, Joyce Man-Fong Lee, Daniel Wai-Hung Ho, Irene Oi-Lin Ng
Background & Aims: The mechanisms underlying metabolic dysfunction-associated steatohepatitis (MASH)-associated hepatocellular carcinoma (HCC) are poorly understood, and effective treatments are lacking. This study explored the translational potential of Resmetirom, a clinically approved thyroid hormone receptor-beta (Thrb) agonist and investigated the mechanistic basis of MASH-associated hepatocarcinogenesis. Approach & Results: Repurposing Resmetirom for MASH-HCC treatment demonstrated significant tumor-suppressive effects across multiple preclinical models. To further investigate its mechanisms, we employed a Western diet plus CCl₄-induced murine MASH-HCC model, complemented by single-cell RNA sequencing (scRNA-seq) analyses of liver and tumor tissues. These analyses revealed active cell-cell communication within the tumor microenvironment, particularly involving hepatic stellate cells (HSCs) and dysplastic hepatocytes (dys-Heps). These cells showed marked upregulation of midkine (MDK), which in human HCC correlated with shorter relapse-free survival, specifically in non-viral, non-alcohol-related cases. In mouse models, MDK facilitated M2-like macrophage polarization via interaction with the receptor LRP1, contributing to disease progression from MASH to fibrosis and eventual HCC. Silencing LRP1 in macrophages abolished MDK-driven M2 polarization and increased cytotoxic cytokine secretion, while LRP1-positive macrophages contributed to T cell exhaustion through the CXCL16-CXCR6 axis. MDK expression negatively correlated with Thrb and lipolytic genes, but positively with lipogenesis genes. Resmetirom treatment not only significantly suppressed tumor growth and reduced steatosis but also decreased MDK expression and increased Thrb levels. Combining Resmetirom and an MDK inhibitor (iMDK) synergistically suppressed tumorigenesis in vivo. Conclusions: Targeting the MDK/LRP1 axis with Resmetirom offers a promising therapeutic strategy for MASH-associated HCC, addressing both metabolic dysfunction and tumor progression.
{"title":"Repurposing resmetirom suppresses MASH-associated hepatocellular carcinoma, with mechanistic implications of MDK/LRP1-mediated metabolic reprogramming and immunosuppression","authors":"Vanilla Xin Zhang, Tina Suoangbaji, Yu‑Man Tsui, Karen Man-Fong Sze, Eva Lee, Lu Tian, Jingyi Lu, Huan Deng, Abdullah Husain, Charry Shuk-Ching Hui, Joyce Man-Fong Lee, Daniel Wai-Hung Ho, Irene Oi-Lin Ng","doi":"10.1097/hep.0000000000001675","DOIUrl":"https://doi.org/10.1097/hep.0000000000001675","url":null,"abstract":"Background & Aims: The mechanisms underlying metabolic dysfunction-associated steatohepatitis (MASH)-associated hepatocellular carcinoma (HCC) are poorly understood, and effective treatments are lacking. This study explored the translational potential of Resmetirom, a clinically approved thyroid hormone receptor-beta (Thrb) agonist and investigated the mechanistic basis of MASH-associated hepatocarcinogenesis. Approach & Results: Repurposing Resmetirom for MASH-HCC treatment demonstrated significant tumor-suppressive effects across multiple preclinical models. To further investigate its mechanisms, we employed a Western diet plus CCl₄-induced murine MASH-HCC model, complemented by single-cell RNA sequencing (scRNA-seq) analyses of liver and tumor tissues. These analyses revealed active cell-cell communication within the tumor microenvironment, particularly involving hepatic stellate cells (HSCs) and dysplastic hepatocytes (dys-Heps). These cells showed marked upregulation of midkine (MDK), which in human HCC correlated with shorter relapse-free survival, specifically in non-viral, non-alcohol-related cases. In mouse models, MDK facilitated M2-like macrophage polarization via interaction with the receptor LRP1, contributing to disease progression from MASH to fibrosis and eventual HCC. Silencing LRP1 in macrophages abolished MDK-driven M2 polarization and increased cytotoxic cytokine secretion, while LRP1-positive macrophages contributed to T cell exhaustion through the CXCL16-CXCR6 axis. MDK expression negatively correlated with Thrb and lipolytic genes, but positively with lipogenesis genes. Resmetirom treatment not only significantly suppressed tumor growth and reduced steatosis but also decreased MDK expression and increased Thrb levels. Combining Resmetirom and an MDK inhibitor (iMDK) synergistically suppressed tumorigenesis in vivo. Conclusions: Targeting the MDK/LRP1 axis with Resmetirom offers a promising therapeutic strategy for MASH-associated HCC, addressing both metabolic dysfunction and tumor progression.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"39 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1097/hep.0000000000001668
Boyan Liu,Heran Li
{"title":"Letter to the Editor: The PNPLA3 paradox: Does genotype modify the clinical utility of the MASLD framework in children.","authors":"Boyan Liu,Heran Li","doi":"10.1097/hep.0000000000001668","DOIUrl":"https://doi.org/10.1097/hep.0000000000001668","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"397 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1097/hep.0000000000001666
Qing-Bao Jiang,Guo-Ming Zhang
{"title":"Letter to the editor: Interpreting the clinical decision value of glycomic-based models for early HCC detection in CHB.","authors":"Qing-Bao Jiang,Guo-Ming Zhang","doi":"10.1097/hep.0000000000001666","DOIUrl":"https://doi.org/10.1097/hep.0000000000001666","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"7 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-08-13DOI: 10.1097/HEP.0000000000001491
Chien-Hao Huang, Wei-Ting Ku, Wei Teng, Wen-Juei Jeng, Chun-Yen Lin
{"title":"Letter to the Editor: Peripheral Foxp3-high Tregs as a dual biomarker for HCC prognosis and immunotherapy response.","authors":"Chien-Hao Huang, Wei-Ting Ku, Wei Teng, Wen-Juei Jeng, Chun-Yen Lin","doi":"10.1097/HEP.0000000000001491","DOIUrl":"10.1097/HEP.0000000000001491","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"E13-E14"},"PeriodicalIF":15.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-19DOI: 10.1097/HEP.0000000000001588
Elsa Gomez-Escobar, Nicol Flores, Naglaa H Shoukry
{"title":"Erratum: One step closer to a pan-genotypic hepatitis C vaccine.","authors":"Elsa Gomez-Escobar, Nicol Flores, Naglaa H Shoukry","doi":"10.1097/HEP.0000000000001588","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001588","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"83 1","pages":"E72"},"PeriodicalIF":15.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2024-07-19DOI: 10.1097/HEP.0000000000001028
Benjamin Koh, Jieling Xiao, Cheng Han Ng, Michelle Law, Shyna Zhuoying Gunalan, Pojsakorn Danpanichkul, Vijay Ramadoss, Benedix Kuan Loon Sim, En Ying Tan, Chong Boon Teo, Benjamin Nah, Margaret Teng, Karn Wijarnpreecha, Yuya Seko, Mei Chin Lim, Hirokazu Takahashi, Atsushi Nakajima, Mazen Noureddin, Mark Muthiah, Daniel Q Huang, Rohit Loomba
Background and aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver disease. Dynamic changes in MRI proton-density-fat fraction (PDFF) are associated with MASH resolution. We aimed to determine the relative efficacy of therapeutic agents for reducing hepatic fat, assessed by MRI-PDFF.
Approach and results: In this systematic review and network meta-analysis, we searched MEDLINE and Embase from inception until December 26, 2023, for published randomized controlled trials comparing pharmacological interventions in patients with MASH that assessed changes in MRI-PDFF. The primary outcome was the absolute change in MRI-PDFF. The secondary outcome was a ≥30% decline in MRI-PDFF. A surface under-the-curve cumulative ranking probabilities (SUCRA) analysis was performed. Of 1550 records, a total of 39 randomized controlled trials (3311 participants) met the inclusion criteria. For MRI-PDFF decline at 24 weeks, aldafermin (SUCRA: 83.65), pegozafermin (SUCRA: 83.46), and pioglitazone (SUCRA: 71.67) were ranked the most effective interventions. At 24 weeks, efinopegdutide (SUCRA: 67.02), semaglutide + firsocostat (SUCRA: 62.43), and pegbelfermin (SUCRA: 61.68) were ranked the most effective interventions for achieving a ≥30% decline in MRI-PDFF.
Conclusions: This study provides an updated, relative rank-order efficacy of therapies for MASH in reducing hepatic fat. These data may help inform the design and sample size calculation of future clinical trials and assist in the selection of combination therapy.
{"title":"Comparative efficacy of pharmacologic therapies for MASH in reducing liver fat content: Systematic review and network meta-analysis.","authors":"Benjamin Koh, Jieling Xiao, Cheng Han Ng, Michelle Law, Shyna Zhuoying Gunalan, Pojsakorn Danpanichkul, Vijay Ramadoss, Benedix Kuan Loon Sim, En Ying Tan, Chong Boon Teo, Benjamin Nah, Margaret Teng, Karn Wijarnpreecha, Yuya Seko, Mei Chin Lim, Hirokazu Takahashi, Atsushi Nakajima, Mazen Noureddin, Mark Muthiah, Daniel Q Huang, Rohit Loomba","doi":"10.1097/HEP.0000000000001028","DOIUrl":"10.1097/HEP.0000000000001028","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver disease. Dynamic changes in MRI proton-density-fat fraction (PDFF) are associated with MASH resolution. We aimed to determine the relative efficacy of therapeutic agents for reducing hepatic fat, assessed by MRI-PDFF.</p><p><strong>Approach and results: </strong>In this systematic review and network meta-analysis, we searched MEDLINE and Embase from inception until December 26, 2023, for published randomized controlled trials comparing pharmacological interventions in patients with MASH that assessed changes in MRI-PDFF. The primary outcome was the absolute change in MRI-PDFF. The secondary outcome was a ≥30% decline in MRI-PDFF. A surface under-the-curve cumulative ranking probabilities (SUCRA) analysis was performed. Of 1550 records, a total of 39 randomized controlled trials (3311 participants) met the inclusion criteria. For MRI-PDFF decline at 24 weeks, aldafermin (SUCRA: 83.65), pegozafermin (SUCRA: 83.46), and pioglitazone (SUCRA: 71.67) were ranked the most effective interventions. At 24 weeks, efinopegdutide (SUCRA: 67.02), semaglutide + firsocostat (SUCRA: 62.43), and pegbelfermin (SUCRA: 61.68) were ranked the most effective interventions for achieving a ≥30% decline in MRI-PDFF.</p><p><strong>Conclusions: </strong>This study provides an updated, relative rank-order efficacy of therapies for MASH in reducing hepatic fat. These data may help inform the design and sample size calculation of future clinical trials and assist in the selection of combination therapy.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"117-126"},"PeriodicalIF":15.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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