Pub Date : 2026-04-01Epub Date: 2024-06-05DOI: 10.1097/HEP.0000000000000941
Yunwei Zhang, Chunyan Cao, Chaofan Li, Russell G Witt, Hai Huang, Allan Tsung, Hongji Zhang
Liver diseases contribute to ~2 million deaths each year and account for 4% of all deaths globally. Despite various treatment options, the management of liver diseases remains challenging. Physical exercise is a promising nonpharmacological approach to maintain and restore homeostasis and effectively prevent and mitigate liver diseases. In this review, we delve into the mechanisms of physical exercise in preventing and treating liver diseases, highlighting its effects on improving insulin sensitivity, regulating lipid homeostasis, and modulating immune function. In addition, we evaluate the impact of physical exercise on various liver diseases, including liver ischemia/reperfusion injury, cardiogenic liver disease, metabolic dysfunction-associated steatotic liver disease, portal hypertension, cirrhosis, and liver cancer. In conclusion, the review underscores the effectiveness of physical exercise as a beneficial intervention in combating liver diseases.
{"title":"Physical exercise in liver diseases.","authors":"Yunwei Zhang, Chunyan Cao, Chaofan Li, Russell G Witt, Hai Huang, Allan Tsung, Hongji Zhang","doi":"10.1097/HEP.0000000000000941","DOIUrl":"10.1097/HEP.0000000000000941","url":null,"abstract":"<p><p>Liver diseases contribute to ~2 million deaths each year and account for 4% of all deaths globally. Despite various treatment options, the management of liver diseases remains challenging. Physical exercise is a promising nonpharmacological approach to maintain and restore homeostasis and effectively prevent and mitigate liver diseases. In this review, we delve into the mechanisms of physical exercise in preventing and treating liver diseases, highlighting its effects on improving insulin sensitivity, regulating lipid homeostasis, and modulating immune function. In addition, we evaluate the impact of physical exercise on various liver diseases, including liver ischemia/reperfusion injury, cardiogenic liver disease, metabolic dysfunction-associated steatotic liver disease, portal hypertension, cirrhosis, and liver cancer. In conclusion, the review underscores the effectiveness of physical exercise as a beneficial intervention in combating liver diseases.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"915-930"},"PeriodicalIF":15.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11702854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246787","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}
Pub Date : 2026-04-01Epub Date: 2025-11-11DOI: 10.1097/HEP.0000000000001610
Mingchen Xie, Haitao Wu, Jian Xu
{"title":"Letter to the Editor: From risk alert to decision support: Enhancing the clinical value of the AI model for cholangiocarcinoma.","authors":"Mingchen Xie, Haitao Wu, Jian Xu","doi":"10.1097/HEP.0000000000001610","DOIUrl":"10.1097/HEP.0000000000001610","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"E116-E117"},"PeriodicalIF":15.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487322","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 : 2026-04-01Epub Date: 2024-07-01DOI: 10.1097/HEP.0000000000000990
Madhumita Premkumar, Constantine J Karvellas, Anand V Kulkarni, Harish Bhujade, K Rajender Reddy
Hospitalized patients with cirrhosis frequently require critical care management for sepsis, HE, respiratory failure, acute variceal bleeding, acute kidney injury (AKI), shock, and optimization for liver transplantation, while outpatients have unique care considerations. Point-of-care ultrasonography (POCUS) enhances bedside examination of the hepatobiliary system and relevant extrahepatic sites. POCUS includes cardiac US and is used to assess volume status and hemodynamic parameters like cardiac output, systemic vascular resistance, cardiac contractility, and pulmonary artery pressure, which aid in the early and accurate diagnosis of heart failure, cirrhotic cardiomyopathy, porto-pulmonary hypertension, hepatopulmonary syndrome, arrhythmia, and pulmonary embolism. This also helps in fluid management and vasopressor use in the resuscitation of patients with cirrhosis. Lung ultrasound (LUS) can help in differentiating pneumonia, effusion, and edema. Further, US guides interventions such as line placement, drainage of abdominal collections/abscesses, relief of tension pneumothorax, drainage of pleural and pericardial effusions, and biliary drainage in cholangitis. Additionally, its role is essential to assess liver masses foci of sepsis, for appropriate sites for paracentesis, and to assess for vascular disorders such as portal vein or hepatic vein thrombosis. Renal US can identify renal and postrenal causes of AKI and aid in diagnosis of prerenal AKI through volume assessment. In this review, we address the principles and methods of POCUS in hospitalized patients and in outpatients with cirrhosis and discuss the application of this diverse modality in clinical hepatology.
{"title":"Role of point-of-care ultrasound (POCUS) in clinical hepatology.","authors":"Madhumita Premkumar, Constantine J Karvellas, Anand V Kulkarni, Harish Bhujade, K Rajender Reddy","doi":"10.1097/HEP.0000000000000990","DOIUrl":"10.1097/HEP.0000000000000990","url":null,"abstract":"<p><p>Hospitalized patients with cirrhosis frequently require critical care management for sepsis, HE, respiratory failure, acute variceal bleeding, acute kidney injury (AKI), shock, and optimization for liver transplantation, while outpatients have unique care considerations. Point-of-care ultrasonography (POCUS) enhances bedside examination of the hepatobiliary system and relevant extrahepatic sites. POCUS includes cardiac US and is used to assess volume status and hemodynamic parameters like cardiac output, systemic vascular resistance, cardiac contractility, and pulmonary artery pressure, which aid in the early and accurate diagnosis of heart failure, cirrhotic cardiomyopathy, porto-pulmonary hypertension, hepatopulmonary syndrome, arrhythmia, and pulmonary embolism. This also helps in fluid management and vasopressor use in the resuscitation of patients with cirrhosis. Lung ultrasound (LUS) can help in differentiating pneumonia, effusion, and edema. Further, US guides interventions such as line placement, drainage of abdominal collections/abscesses, relief of tension pneumothorax, drainage of pleural and pericardial effusions, and biliary drainage in cholangitis. Additionally, its role is essential to assess liver masses foci of sepsis, for appropriate sites for paracentesis, and to assess for vascular disorders such as portal vein or hepatic vein thrombosis. Renal US can identify renal and postrenal causes of AKI and aid in diagnosis of prerenal AKI through volume assessment. In this review, we address the principles and methods of POCUS in hospitalized patients and in outpatients with cirrhosis and discuss the application of this diverse modality in clinical hepatology.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"931-947"},"PeriodicalIF":15.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490144","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 : 2026-04-01Epub Date: 2025-11-11DOI: 10.1097/HEP.0000000000001611
Yashbir Singh, John E Eaton, Bradley J Erickson, Gregory J Gores
{"title":"Reply: From risk alert to decision support: Enhancing the clinical value of the AI model for cholangiocarcinoma.","authors":"Yashbir Singh, John E Eaton, Bradley J Erickson, Gregory J Gores","doi":"10.1097/HEP.0000000000001611","DOIUrl":"10.1097/HEP.0000000000001611","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"E118-E119"},"PeriodicalIF":15.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487239","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 : 2026-04-01Epub Date: 2025-11-04DOI: 10.1097/HEP.0000000000001607
{"title":"Updated AASLD Guidelines for Chronic Hepatitis B Treatment.","authors":"","doi":"10.1097/HEP.0000000000001607","DOIUrl":"10.1097/HEP.0000000000001607","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"970-973"},"PeriodicalIF":15.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686621","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 : 2026-04-01Epub Date: 2024-07-24DOI: 10.1097/HEP.0000000000000987
Gopanandan Parthasarathy, Harmeet Malhi, Jasmohan S Bajaj
Myriad associations between the microbiome and various facets of liver physiology and pathology have been described in the literature. Building on descriptive and correlative sequencing studies, metagenomic studies are expanding our collective understanding of the functional and mechanistic role of the microbiome as mediators of the gut-liver axis. Based on these mechanisms, the functional activity of the microbiome represents an attractive, tractable, and precision medicine therapeutic target in several liver diseases. Indeed, several therapeutics have been used in liver disease even before their description as a microbiome-dependent approach. To bring successful microbiome-targeted and microbiome-inspired therapies to the clinic, a comprehensive appreciation of the different approaches to influence, collaborate with, or engineer the gut microbiome to coopt a disease-relevant function of interest in the right patient is key. Herein, we describe the various levels at which the microbiome can be targeted-from prebiotics, probiotics, synbiotics, and antibiotics to microbiome reconstitution and precision microbiome engineering. Assimilating data from preclinical animal models, human studies as well as clinical trials, we describe the potential for and rationale behind studying such therapies across several liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cirrhosis, HE as well as liver cancer. Lastly, we discuss lessons learned from previous attempts at developing such therapies, the regulatory framework that needs to be navigated, and the challenges that remain.
{"title":"Therapeutic manipulation of the microbiome in liver disease.","authors":"Gopanandan Parthasarathy, Harmeet Malhi, Jasmohan S Bajaj","doi":"10.1097/HEP.0000000000000987","DOIUrl":"10.1097/HEP.0000000000000987","url":null,"abstract":"<p><p>Myriad associations between the microbiome and various facets of liver physiology and pathology have been described in the literature. Building on descriptive and correlative sequencing studies, metagenomic studies are expanding our collective understanding of the functional and mechanistic role of the microbiome as mediators of the gut-liver axis. Based on these mechanisms, the functional activity of the microbiome represents an attractive, tractable, and precision medicine therapeutic target in several liver diseases. Indeed, several therapeutics have been used in liver disease even before their description as a microbiome-dependent approach. To bring successful microbiome-targeted and microbiome-inspired therapies to the clinic, a comprehensive appreciation of the different approaches to influence, collaborate with, or engineer the gut microbiome to coopt a disease-relevant function of interest in the right patient is key. Herein, we describe the various levels at which the microbiome can be targeted-from prebiotics, probiotics, synbiotics, and antibiotics to microbiome reconstitution and precision microbiome engineering. Assimilating data from preclinical animal models, human studies as well as clinical trials, we describe the potential for and rationale behind studying such therapies across several liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cirrhosis, HE as well as liver cancer. Lastly, we discuss lessons learned from previous attempts at developing such therapies, the regulatory framework that needs to be navigated, and the challenges that remain.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"948-969"},"PeriodicalIF":15.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454175","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}
Pub Date : 2026-03-24DOI: 10.1097/hep.0000000000001749
Zhuoshuai Liang, Huizhen Jin, Wenhui Gao, Xinmeng Hu, Yingao Xi, Hongrui Zhang, Yi Cheng, Jikang Shi, Yawen Liu
Background & Aims: Effective non-invasive risk-stratification tools are essential for the early detection of individuals at high risk for cirrhosis, to enable timely intervention. We conducted a prospective, head-to-head comparison of fibrosis-based and outcome-driven routine blood-based risk scores for predicting cirrhosis-related morbidity in a large community-based cohort. Approach and Results: We first performed a systematic review to identify risk scores derived from routine liver blood tests, and then evaluated them in the UK Biobank. Severe cirrhosis-related morbidity was defined using International Classification of Diseases, Tenth Revision codes. Discrimination and clinical utility were assessed using the Wolbers C-index, time-dependent area under the receiver operating characteristic curve, area under the precision–recall curve (AUPRC), and cumulative incidence accounting for competing risks. The review identified 12 eligible risk scores (10 novel models plus APRI and FIB-4). Among 385,738 participants, the 10-year cumulative incidence of severe cirrhosis-related morbidity was 0.39% (1,498 events). Most novel scores outperformed APRI and FIB-4. LiverRisk showed the highest discrimination at 5 years (C-index 0.847) and 10 years (C-index 0.812), closely followed by CORE (5-year C-index 0.839; 10-year C-index 0.811). In contrast, CORE achieved better enrichment of high-risk individuals, with an AUPRC of 0.088 compared with 0.063 for LiverRisk. At low referral proportions, increasing the CORE threshold yielded greater net benefit than a sequential CORE-LiverRisk referral strategy. Conclusion: CORE and LiverRisk are the most discriminative routine blood-based tools for predicting long-term cirrhosis-related morbidity in the community. When referrals are limited, a higher-threshold CORE-only strategy may outperform a sequential CORE-LiverRisk approach.
{"title":"Prospective head-to-head comparison of routine non-invasive scores for predicting severe cirrhosis-related morbidity in the general population","authors":"Zhuoshuai Liang, Huizhen Jin, Wenhui Gao, Xinmeng Hu, Yingao Xi, Hongrui Zhang, Yi Cheng, Jikang Shi, Yawen Liu","doi":"10.1097/hep.0000000000001749","DOIUrl":"https://doi.org/10.1097/hep.0000000000001749","url":null,"abstract":"Background & Aims: Effective non-invasive risk-stratification tools are essential for the early detection of individuals at high risk for cirrhosis, to enable timely intervention. We conducted a prospective, head-to-head comparison of fibrosis-based and outcome-driven routine blood-based risk scores for predicting cirrhosis-related morbidity in a large community-based cohort. Approach and Results: We first performed a systematic review to identify risk scores derived from routine liver blood tests, and then evaluated them in the UK Biobank. Severe cirrhosis-related morbidity was defined using International Classification of Diseases, Tenth Revision codes. Discrimination and clinical utility were assessed using the Wolbers C-index, time-dependent area under the receiver operating characteristic curve, area under the precision–recall curve (AUPRC), and cumulative incidence accounting for competing risks. The review identified 12 eligible risk scores (10 novel models plus APRI and FIB-4). Among 385,738 participants, the 10-year cumulative incidence of severe cirrhosis-related morbidity was 0.39% (1,498 events). Most novel scores outperformed APRI and FIB-4. LiverRisk showed the highest discrimination at 5 years (C-index 0.847) and 10 years (C-index 0.812), closely followed by CORE (5-year C-index 0.839; 10-year C-index 0.811). In contrast, CORE achieved better enrichment of high-risk individuals, with an AUPRC of 0.088 compared with 0.063 for LiverRisk. At low referral proportions, increasing the CORE threshold yielded greater net benefit than a sequential CORE-LiverRisk referral strategy. Conclusion: CORE and LiverRisk are the most discriminative routine blood-based tools for predicting long-term cirrhosis-related morbidity in the community. When referrals are limited, a higher-threshold CORE-only strategy may outperform a sequential CORE-LiverRisk approach.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"405 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506775","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 and Aims: Hepatitis B virus (HBV) infection exhibits marked cellular heterogeneity, which conventional poly(A)-based single-cell RNA sequencing fails to resolve this heterogeneity owing to the overwhelming host transcript background. To overcome this, we developed B-BEST (HBV can BE Seen on host Transcriptome), a targeted sc/snRNA seq approach using custom beads conjugated with HBV specific probes to simultaneously quantify five viral genomic regions (S, X, pgRNA, rcDNA, cccDNA). Approach and Results: We validated B-BEST in HepAD38 cells and integrated it with long-read sequencing, spatial transcriptomics, and in situ hybridization in liver tissues from treatment-naïve patients and antiviral treated humanized liver chimeric (Hu-URG) mice. B-BEST revealed significant heterogeneity among HBV-positive hepatocytes. In HBeAg-positive patients, HBV-positive subpopulations enriched for hepatic synthesis/metabolism and mitochondrial function were linked to active viral replication and transcription, with only a mild type I interferon response. Severe inflammation correlated with suppressed HBV replication. Long-read sequencing indicated that integrated HBV transcripts preferentially used host promoters and contributed to HBsAg persistence in HBeAg-negative patients. In Hu URG mice, entecavir upregulated metabolic pathways, while peginterferon alfa-2b induced broad spectrum antiviral programs. Notably, clonal expansion of hepatocytes diluted the intrahepatic viral reservoir when viral replication was inhibited, suggesting a proliferative dilution mechanism that may contribute to functional cure. Conclusions: In summary, our B-BEST platform provides resources for delineating the heterogeneous landscape of HBV infection, identifying host determinants and microenvironmental factors that govern viral replication and persistence, and highlighting hepatocyte proliferation as a potential clearance mechanism for antiviral therapy.
{"title":"Host-viral interaction of HBV infection revealed by single-cell transcriptome jointly profiling the viral replication state","authors":"Yanfang Huang, Hongyuan Xue, Jinhang He, Rongshan Fan, Yongping Liu, Miaoqu Zhang, Zunguo Du, Zhongliang Shen, Quanbao Zhang, Xiaomu Hu, Caixia Zheng, Zhang Xia, Shengran Jiang, Ning Jiang, Wenqi Zhu, Jingshen Wang, Zaoxu Xu, Renjie Liao, Luyang Zhao, Yumeng Zhang, Jianming Zheng, Yuxian Huang, Jiming Zhang, Guojun Li, Zhengxin Wang, Qiran Zhang, Wenhong Zhang, Chao Qiu","doi":"10.1097/hep.0000000000001750","DOIUrl":"https://doi.org/10.1097/hep.0000000000001750","url":null,"abstract":"Background and Aims: Hepatitis B virus (HBV) infection exhibits marked cellular heterogeneity, which conventional poly(A)-based single-cell RNA sequencing fails to resolve this heterogeneity owing to the overwhelming host transcript background. To overcome this, we developed B-BEST (HBV can BE Seen on host Transcriptome), a targeted sc/snRNA seq approach using custom beads conjugated with HBV specific probes to simultaneously quantify five viral genomic regions (S, X, pgRNA, rcDNA, cccDNA). Approach and Results: We validated B-BEST in <jats:italic toggle=\"yes\">HepAD38</jats:italic> cells and integrated it with long-read sequencing, spatial transcriptomics, and <jats:italic toggle=\"yes\">in situ</jats:italic> hybridization in liver tissues from treatment-naïve patients and antiviral treated humanized liver chimeric (Hu-URG) mice. B-BEST revealed significant heterogeneity among HBV-positive hepatocytes. In HBeAg-positive patients, HBV-positive subpopulations enriched for hepatic synthesis/metabolism and mitochondrial function were linked to active viral replication and transcription, with only a mild type I interferon response. Severe inflammation correlated with suppressed HBV replication. Long-read sequencing indicated that integrated HBV transcripts preferentially used host promoters and contributed to HBsAg persistence in HBeAg-negative patients. In Hu URG mice, entecavir upregulated metabolic pathways, while peginterferon alfa-2b induced broad spectrum antiviral programs. Notably, clonal expansion of hepatocytes diluted the intrahepatic viral reservoir when viral replication was inhibited, suggesting a proliferative dilution mechanism that may contribute to functional cure. Conclusions: In summary, our B-BEST platform provides resources for delineating the heterogeneous landscape of HBV infection, identifying host determinants and microenvironmental factors that govern viral replication and persistence, and highlighting hepatocyte proliferation as a potential clearance mechanism for antiviral therapy.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"35 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506776","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 : 2026-03-19DOI: 10.1097/hep.0000000000001747
Ye Cheng,Zhong-Die Li,Zhi-Hong Guan,Li Wang,Yi-Ling Qiu,Wei-Yuan Fang,Jing Zhao,Kun Zhang,Jia-Qi Li,Qing-He Xing,Jian-She Wang
BACKGROUND AIMSSince DNA sequencing alone faces challenges in variant interpretation during genetic diagnosis, RNA sequencing has recently gained attention in resolving these diagnostic gaps. This study aimed to evaluate the advantages of liver tissue RNA sequencing in the diagnosis of genetic liver diseases.APPROACH RESULTLiver tissue RNA sequencing was performed on 147 patients with prior DNA sequencing. We evaluated the role of RNA sequencing by analyzing aberrant gene expression, splicing, allele-specific expression, transcript-level similarity and mosaic variants. Liver RNA-seq supported the molecular diagnoses in 56 patients diagnosed by DNA sequencing alone. Among 91 previously undiagnosed patients, incorporating RNA sequencing established a diagnosis in 17 (18.68%) patients. Among the 33 patients with indicative clinical phenotypes or prioritized variants, diagnosis was established in 15 (45.45%) patients under the help of RNA sequencing. This improvement was primarily (16/17) driven by the detection of aberrant splicing and allele-specific expression, instead of aberrant expression. RNA sequencing revealed ±50bp of cryptic splicing sites as hotspot regions, characterized allele-specific expression at both the gene and variant levels and revealed shared transcriptomic features in low GGT cholestasis.CONCLUSIONSWhile DNA sequencing demonstrates superior sensitivity in detecting clinically relevant variants, liver RNA sequencing significantly enhances genetic diagnosis mainly by revealing aberrant splicing and allele-specific expression. These findings suggest that RNA sequencing is an essential complement to DNA sequencing.
{"title":"Liver transcriptome sequencing contributes to the molecular diagnosis of genetic liver diseases.","authors":"Ye Cheng,Zhong-Die Li,Zhi-Hong Guan,Li Wang,Yi-Ling Qiu,Wei-Yuan Fang,Jing Zhao,Kun Zhang,Jia-Qi Li,Qing-He Xing,Jian-She Wang","doi":"10.1097/hep.0000000000001747","DOIUrl":"https://doi.org/10.1097/hep.0000000000001747","url":null,"abstract":"BACKGROUND AIMSSince DNA sequencing alone faces challenges in variant interpretation during genetic diagnosis, RNA sequencing has recently gained attention in resolving these diagnostic gaps. This study aimed to evaluate the advantages of liver tissue RNA sequencing in the diagnosis of genetic liver diseases.APPROACH RESULTLiver tissue RNA sequencing was performed on 147 patients with prior DNA sequencing. We evaluated the role of RNA sequencing by analyzing aberrant gene expression, splicing, allele-specific expression, transcript-level similarity and mosaic variants. Liver RNA-seq supported the molecular diagnoses in 56 patients diagnosed by DNA sequencing alone. Among 91 previously undiagnosed patients, incorporating RNA sequencing established a diagnosis in 17 (18.68%) patients. Among the 33 patients with indicative clinical phenotypes or prioritized variants, diagnosis was established in 15 (45.45%) patients under the help of RNA sequencing. This improvement was primarily (16/17) driven by the detection of aberrant splicing and allele-specific expression, instead of aberrant expression. RNA sequencing revealed ±50bp of cryptic splicing sites as hotspot regions, characterized allele-specific expression at both the gene and variant levels and revealed shared transcriptomic features in low GGT cholestasis.CONCLUSIONSWhile DNA sequencing demonstrates superior sensitivity in detecting clinically relevant variants, liver RNA sequencing significantly enhances genetic diagnosis mainly by revealing aberrant splicing and allele-specific expression. These findings suggest that RNA sequencing is an essential complement to DNA sequencing.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"13 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483391","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 AND AIMSHepatic stellate cell (HSC) activation is central to liver fibrosis, but emerging evidence suggests HSC homeostatic activity. We compared HSC functions in parenchymal injury (CCl₄-driven) versus metabolic dysfunction-associated steatohepatitis (MASH; choline deficient high fat diet, CD-HFD) and identify therapeutic targets preserving HSC homeostatic functions.APPROACH AND RESULTSInducible HSC ablation was performed in Lrat-iDTR mice during active fibrogenesis. Multi-parametric analyses were conducted to assess roles of HSCs in two established fibrosis models, with a focus on elucidating the cellular origins of myofibroblasts and the alterations in regeneration and ductular reaction. RNA-seq from human biopsies validated mechanisms. HSC depletion in the CD-HFD model not only exacerbated MASH but also elevated a-SMA+ myofibroblasts derived from PDGFRα⁺ portal fibroblasts, impaired hepatocyte function (metabolic zonation and regeneration), and enhanced the ductular reaction. Conversely, HSC depletion in the CCl₄ model attenuated fibrosis without affecting hepatic regeneration or metabolic zonation. Strikingly, 85.5% of quiescent HSCs-enriched genes remained upregulated in MASH-associated HSCs, unlike in CCl4 fibrosis. RNA-seq followed by in vivo studies identified extracellular matrix protein 1 (ECM1), as a master regulator of HSC quiescence, and HSC-specific ECM1 overexpression suppressed CCl₄-induced fibrosis. In human biopsies (MASH, HBV, PBC, PSC), ECM1 expression inversely correlated with fibrosis stage.CONCLUSIONSHSCs exhibit dual roles contingent on disease context: in MASH with moderate inflammation, they maintain homeostasis, whereas in massive CCl₄-driven injury, activated HSCs promote fibrogenesis. ECM1 enforces HSC quiescence and facilitates fibrosis resolution. Antifibrotic therapies based on general HSC ablation may be harmful.
{"title":"ECM1 produced by hepatic stellate cells serves as gate keeper of liver homeostasis in hepatic fibrosis.","authors":"Aiting Yang,Xuzhen Yan,Yiwen Wang,Qi Han,Xiaofei Tong,Shuyan Chen,Xinyu Zhao,Wei Chen,Jidong Jia,Detlef Schuppan,Hong You","doi":"10.1097/hep.0000000000001715","DOIUrl":"https://doi.org/10.1097/hep.0000000000001715","url":null,"abstract":"BACKGROUND AND AIMSHepatic stellate cell (HSC) activation is central to liver fibrosis, but emerging evidence suggests HSC homeostatic activity. We compared HSC functions in parenchymal injury (CCl₄-driven) versus metabolic dysfunction-associated steatohepatitis (MASH; choline deficient high fat diet, CD-HFD) and identify therapeutic targets preserving HSC homeostatic functions.APPROACH AND RESULTSInducible HSC ablation was performed in Lrat-iDTR mice during active fibrogenesis. Multi-parametric analyses were conducted to assess roles of HSCs in two established fibrosis models, with a focus on elucidating the cellular origins of myofibroblasts and the alterations in regeneration and ductular reaction. RNA-seq from human biopsies validated mechanisms. HSC depletion in the CD-HFD model not only exacerbated MASH but also elevated a-SMA+ myofibroblasts derived from PDGFRα⁺ portal fibroblasts, impaired hepatocyte function (metabolic zonation and regeneration), and enhanced the ductular reaction. Conversely, HSC depletion in the CCl₄ model attenuated fibrosis without affecting hepatic regeneration or metabolic zonation. Strikingly, 85.5% of quiescent HSCs-enriched genes remained upregulated in MASH-associated HSCs, unlike in CCl4 fibrosis. RNA-seq followed by in vivo studies identified extracellular matrix protein 1 (ECM1), as a master regulator of HSC quiescence, and HSC-specific ECM1 overexpression suppressed CCl₄-induced fibrosis. In human biopsies (MASH, HBV, PBC, PSC), ECM1 expression inversely correlated with fibrosis stage.CONCLUSIONSHSCs exhibit dual roles contingent on disease context: in MASH with moderate inflammation, they maintain homeostasis, whereas in massive CCl₄-driven injury, activated HSCs promote fibrogenesis. ECM1 enforces HSC quiescence and facilitates fibrosis resolution. Antifibrotic therapies based on general HSC ablation may be harmful.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"6 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483392","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}