Pub Date : 2024-11-12DOI: 10.1097/hep.0000000000001165
Chunyuan Zhao, Wei Zhao
{"title":"Utilizing of viral RNA fragment to limit acute inflammation","authors":"Chunyuan Zhao, Wei Zhao","doi":"10.1097/hep.0000000000001165","DOIUrl":"https://doi.org/10.1097/hep.0000000000001165","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"31 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599744","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 : 2024-11-12DOI: 10.1097/hep.0000000000001158
Jia Jian Loh, Kai Yu Ng, Ianto Bosheng Huang, Mingdan Deng, Yanyan Wang, Ki Fong Man, Ka Hei Lam, Terence Kin-Wah Lee, Jia Yan Tan, Yalu Cui, Huajian Yu, Tin Lok Wong, Yuan Gao, Jing-Ping Yun, Stephanie Ma
Hepatocellular carcinoma (HCC) is characterized by metabolic pathway aberrations, which enable cancer cells to meet their energy demands and accelerate malignant progression. Identifying novel metabolic players governing therapy resistance and self-renewal in HCC is crucial, as these properties are likely responsible for tumor recurrence. Clinical traits and RNA-seq of HCC patients in TCGA were used for weighted gene co-expression network analysis, where one module was significantly correlated with advanced pathological stage and stem cell population maintenance. Further analysis of this module by integrating data obtained from HCC patient nonresponders to tyrosine kinase inhibitors identified 361 commonly deregulated genes significantly enriched in the intracellular signal transduction pathway, with diacylglycerol kinase eta (DGKH) ranked as the most enriched gene in poorly differentiated HCC tumors. Clinically, DGKH was elevated in tumor tissues compared to non-tumor tissues. Patients with higher DGKH expression exhibited a more undifferentiated state and were less responsive to TKIs. Functional assays using DGKH-manipulated HCC cell lines demonstrated that DGKH augmented aggressive features, including cancer stemness, therapy resistance, and metastasis. Upstream of DGKH, we discovered that the E1A-associated protein p300 (EP300) binds to DGKH’s promoter region, thereby increasing its transcriptomic expression. Mechanistically, DGKH promotes mTOR signaling by producing phosphatidic acid (PA). In an immunocompetent mouse model, co-treatment with sorafenib and liver-directed AAV8-mediated Dgkh depletion significantly reduced tumor burden, self-renewal, PA production and mTOR signaling. Our research demonstrated that DGKH is a crucial oncometabolic regulator of cancer stemness and therapy resistance, inhibition of which may lead to more effective hepatocellular carcinoma treatment.
{"title":"DGKH-mediated phosphatidic acid oncometabolism as a driver of self-renewal and therapy resistance in hepatocellular carcinoma","authors":"Jia Jian Loh, Kai Yu Ng, Ianto Bosheng Huang, Mingdan Deng, Yanyan Wang, Ki Fong Man, Ka Hei Lam, Terence Kin-Wah Lee, Jia Yan Tan, Yalu Cui, Huajian Yu, Tin Lok Wong, Yuan Gao, Jing-Ping Yun, Stephanie Ma","doi":"10.1097/hep.0000000000001158","DOIUrl":"https://doi.org/10.1097/hep.0000000000001158","url":null,"abstract":"Hepatocellular carcinoma (HCC) is characterized by metabolic pathway aberrations, which enable cancer cells to meet their energy demands and accelerate malignant progression. Identifying novel metabolic players governing therapy resistance and self-renewal in HCC is crucial, as these properties are likely responsible for tumor recurrence. Clinical traits and RNA-seq of HCC patients in TCGA were used for weighted gene co-expression network analysis, where one module was significantly correlated with advanced pathological stage and stem cell population maintenance. Further analysis of this module by integrating data obtained from HCC patient nonresponders to tyrosine kinase inhibitors identified 361 commonly deregulated genes significantly enriched in the intracellular signal transduction pathway, with diacylglycerol kinase eta (DGKH) ranked as the most enriched gene in poorly differentiated HCC tumors. Clinically, DGKH was elevated in tumor tissues compared to non-tumor tissues. Patients with higher DGKH expression exhibited a more undifferentiated state and were less responsive to TKIs. Functional assays using DGKH-manipulated HCC cell lines demonstrated that DGKH augmented aggressive features, including cancer stemness, therapy resistance, and metastasis. Upstream of <jats:italic toggle=\"yes\">DGKH</jats:italic>, we discovered that the E1A-associated protein p300 (EP300) binds to DGKH’s promoter region, thereby increasing its transcriptomic expression. Mechanistically, DGKH promotes mTOR signaling by producing phosphatidic acid (PA). In an immunocompetent mouse model, co-treatment with sorafenib and liver-directed AAV8-mediated <jats:italic toggle=\"yes\">Dgkh</jats:italic> depletion significantly reduced tumor burden, self-renewal, PA production and mTOR signaling. Our research demonstrated that DGKH is a crucial oncometabolic regulator of cancer stemness and therapy resistance, inhibition of which may lead to more effective hepatocellular carcinoma treatment.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"56 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601301","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 : 2024-11-12DOI: 10.1097/hep.0000000000001160
Blanca Simón-Codina, Júlia Cacho-Pujol, Anna Moles, Pedro Melgar-Lesmes
Cutting-edge research has expanded our understanding of the macrophage activation programs in liver diseases making this immune cell type a therapeutic target. Clinical data on macrophage infiltration and polarization states have been used to help predict mortality or poor prognosis in patients with liver cirrhosis and/or hepatocellular carcinoma. The latest single-cell and spatial transcriptomics studies have dissected unforeseen aspects depicting the immense heterogeneity of macrophages and their multifaceted role on both promoting and resolving hepatic inflammation, injury, and fibrosis. Hepatic macrophages (resident tissue Kupffer cells and monocyte-derived macrophages) display such plasticity and phenotypic diversity that macrophages with antagonistic functions may coexist in adjacent regions of the liver. In this scenario, the analysis of macrophage-derived inflammatory and anti-inflammatory circulating soluble markers in patients with liver disease only offers a partial picture of the full complexity of the hepatic macrophage subsets. The reprogramming of macrophages involves understanding the multiple regulatory mechanisms and diverse populations of hepatic macrophages and the design of macrophage-targeted therapeutic interventions to restore hepatic homeostasis. Here we review the potential targets to modulate macrophage behavior in liver diseases and nanoscale therapeutics that aim to target and treat macrophages. We will summarize current knowledge on the diverse macrophage programs activated in chronic liver inflammation, cirrhosis and hepatocellular carcinoma that may be of therapeutic interest for precision medicine.
{"title":"Reprogramming macrophages to treat liver diseases","authors":"Blanca Simón-Codina, Júlia Cacho-Pujol, Anna Moles, Pedro Melgar-Lesmes","doi":"10.1097/hep.0000000000001160","DOIUrl":"https://doi.org/10.1097/hep.0000000000001160","url":null,"abstract":"Cutting-edge research has expanded our understanding of the macrophage activation programs in liver diseases making this immune cell type a therapeutic target. Clinical data on macrophage infiltration and polarization states have been used to help predict mortality or poor prognosis in patients with liver cirrhosis and/or hepatocellular carcinoma. The latest single-cell and spatial transcriptomics studies have dissected unforeseen aspects depicting the immense heterogeneity of macrophages and their multifaceted role on both promoting and resolving hepatic inflammation, injury, and fibrosis. Hepatic macrophages (resident tissue Kupffer cells and monocyte-derived macrophages) display such plasticity and phenotypic diversity that macrophages with antagonistic functions may coexist in adjacent regions of the liver. In this scenario, the analysis of macrophage-derived inflammatory and anti-inflammatory circulating soluble markers in patients with liver disease only offers a partial picture of the full complexity of the hepatic macrophage subsets. The reprogramming of macrophages involves understanding the multiple regulatory mechanisms and diverse populations of hepatic macrophages and the design of macrophage-targeted therapeutic interventions to restore hepatic homeostasis. Here we review the potential targets to modulate macrophage behavior in liver diseases and nanoscale therapeutics that aim to target and treat macrophages. We will summarize current knowledge on the diverse macrophage programs activated in chronic liver inflammation, cirrhosis and hepatocellular carcinoma that may be of therapeutic interest for precision medicine.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"95 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601298","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 : 2024-11-12DOI: 10.1097/hep.0000000000001166
Cynthia Levy, Christopher L. Bowlus
Primary biliary cholangitis (PBC) is an enigmatic, autoimmune disease targeting the small intralobular bile ducts resulting in cholestasis and potentially progression to biliary cirrhosis. Primarily affecting middle-aged women, the diagnosis of PBC is typically straightforward with most patients presenting with cholestatic liver tests and the highly specific anti-mitochondrial antibody. For decades, the foundational treatment of PBC has been ursodeoxycholic acid (UDCA) which delays disease progression in most patients but has no impact on PBC symptoms. Large cohort studies of patients with PBC have established the benefit of maximizing the reduction in serum alkaline phosphatase with UDCA and the need to add second-line agents in patients who do not achieve an adequate response. Advances in the understanding of bile acid physiology have led to the development of new agents that improve cholestasis in patients with PBC and are predicted to reduce the risk of disease progression. Obeticholic acid, the first second-line therapy to be approved for PBC, significantly improves liver biochemistries and has been associated with improved long term clinical outcomes but is limited by its propensity to induce pruritus. Elafibranor and seladelpar are peroxisome proliferator-activated receptor agonists recently approved for use in patient with PBC, whereas bezafibrate and fenofibrate are available as off-label therapies. They also have shown biochemical improvements among patients with an inadequate response to UDCA, but may improve symptoms of pruritus. Herein, we review the patient features to consider when deciding whether a second-line agent is indicated and which agent to consider for a truly personalized approach to PBC patient care.
{"title":"Primary Biliary Cholangitis: Personalizing Second-Line Therapies-R1","authors":"Cynthia Levy, Christopher L. Bowlus","doi":"10.1097/hep.0000000000001166","DOIUrl":"https://doi.org/10.1097/hep.0000000000001166","url":null,"abstract":"Primary biliary cholangitis (PBC) is an enigmatic, autoimmune disease targeting the small intralobular bile ducts resulting in cholestasis and potentially progression to biliary cirrhosis. Primarily affecting middle-aged women, the diagnosis of PBC is typically straightforward with most patients presenting with cholestatic liver tests and the highly specific anti-mitochondrial antibody. For decades, the foundational treatment of PBC has been ursodeoxycholic acid (UDCA) which delays disease progression in most patients but has no impact on PBC symptoms. Large cohort studies of patients with PBC have established the benefit of maximizing the reduction in serum alkaline phosphatase with UDCA and the need to add second-line agents in patients who do not achieve an adequate response. Advances in the understanding of bile acid physiology have led to the development of new agents that improve cholestasis in patients with PBC and are predicted to reduce the risk of disease progression. Obeticholic acid, the first second-line therapy to be approved for PBC, significantly improves liver biochemistries and has been associated with improved long term clinical outcomes but is limited by its propensity to induce pruritus. Elafibranor and seladelpar are peroxisome proliferator-activated receptor agonists recently approved for use in patient with PBC, whereas bezafibrate and fenofibrate are available as off-label therapies. They also have shown biochemical improvements among patients with an inadequate response to UDCA, but may improve symptoms of pruritus. Herein, we review the patient features to consider when deciding whether a second-line agent is indicated and which agent to consider for a truly personalized approach to PBC patient care.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"41 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601299","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 : 2024-11-12DOI: 10.1097/hep.0000000000001157
Vidhu V. Thaker, Nancy Crimmins, Katherine P. Yates, Ali Mencin, Stavra Xanthakos
{"title":"Reply: Prevalence of subclinical hypothyroidism and longitudinal thyroid stimulating hormone changes in youth with metabolic dysfunction-associated steatotic liver disease: an observational study","authors":"Vidhu V. Thaker, Nancy Crimmins, Katherine P. Yates, Ali Mencin, Stavra Xanthakos","doi":"10.1097/hep.0000000000001157","DOIUrl":"https://doi.org/10.1097/hep.0000000000001157","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"18 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599746","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 : 2024-11-12DOI: 10.1097/hep.0000000000001152
Yanfei Yang, Jiaqi Yao, Xu Luo, Guang Tan, Chi Ma
{"title":"Letter to editor: Use of HBV RNA and to predict change in serological status and disease activity in CHB","authors":"Yanfei Yang, Jiaqi Yao, Xu Luo, Guang Tan, Chi Ma","doi":"10.1097/hep.0000000000001152","DOIUrl":"https://doi.org/10.1097/hep.0000000000001152","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"107 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601300","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 : 2024-11-11DOI: 10.1097/hep.0000000000001162
Binu V. John, Dustin Bastaich, Bassam Dahman
{"title":"Reply: Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a national cohort","authors":"Binu V. John, Dustin Bastaich, Bassam Dahman","doi":"10.1097/hep.0000000000001162","DOIUrl":"https://doi.org/10.1097/hep.0000000000001162","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"16 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599747","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 : 2024-11-11DOI: 10.1097/hep.0000000000001153
Jake E. Krige, Eduard G. Jonas, Marc M. Bernon
{"title":"Letter to the editor: Quality indicators and the safety profile of endoscopic intervention in patients with bleeding esophageal varices","authors":"Jake E. Krige, Eduard G. Jonas, Marc M. Bernon","doi":"10.1097/hep.0000000000001153","DOIUrl":"https://doi.org/10.1097/hep.0000000000001153","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"216 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599749","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}
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