{"title":"Targeting the ASB3-CPT1A axis-a new player in combating metabolic dysfunction-associated steatotic liver disease.","authors":"Yueying Yang, Ying Yang, Yan Lu","doi":"10.3350/cmh.2025.1013","DOIUrl":"https://doi.org/10.3350/cmh.2025.1013","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":16.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063362","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: Endoplasmic reticulum (ER) stress in hepatocytes plays a causative role in alcohol-associated liver disease (ALD). The incomplete inhibition of ER stress by targeting canonical ER stress sensor proteins suggests the existence of noncanonical ER stress pathways in ALD pathology. This study aimed to delineate the role of RAB25 in ALD and its regulatory mechanism in noncanonical ER stress pathways.
Methods: RAB25 activation was examined in liver samples from ALD patients and ethanol-fed mice. The interaction between RAB25 and GCN1 was confirmed through mass spectrometry and co-immunoprecipitation (Co-IP) assays in vitro. The role of RAB25/GCN1 in promoting noncanonical ER stress in ALD was assessed both in vitro and in vivo.
Results: RAB25 expression was upregulated and specifically accumulated on the endoplasmic reticulum in ALD. Mass spectrometry and Co-IP assays confirmed that RAB25 interacts with GCN1, thereby activating a noncanonical ER stress pathway that facilitates ALD progression. Further analysis revealed that RAB25 interaction with GCN1 inhibits K33-ubiquitination-mediated degradation of GCN1, promotes GCN2 phosphorylation, and subsequently activates ATF4-mediated ER stress. This activation modulates lipid metabolism, mitochondrial function, and inflammation, thereby facilitating ALD progression. Knockdown of RAB25 in hepatocytes inhibited ER stress activation and mitigated associated mitochondrial dysfunction, excessive lipid synthesis, and the exaggerated inflammatory response in an ALD model.
Conclusions: Our findings demonstrate a causal role for RAB25-GCN1 signaling in activating the ER stress pathway, which contributes to ALD progression. This pathway may provide a proof-of-concept target for treating ALD and associated metabolic disorders.
{"title":"RAB25/GCN1 Signaling Promotes ER Stress to Mediate Alcohol-associated Liver Disease Progression.","authors":"Xue-Wen Liu, Zi-Bin Zhan, Ze-Hua Li, Yue Zhang, Xue-Yan Qiao, Xin-Ming Li, Xiang-Jing Liang, Kun-Hao Bai, Xian-Feng Xia, Fan-Hong Zeng, Yi Gao, Jun Weng","doi":"10.3350/cmh.2025.0559","DOIUrl":"https://doi.org/10.3350/cmh.2025.0559","url":null,"abstract":"<p><strong>Background/aims: </strong>Endoplasmic reticulum (ER) stress in hepatocytes plays a causative role in alcohol-associated liver disease (ALD). The incomplete inhibition of ER stress by targeting canonical ER stress sensor proteins suggests the existence of noncanonical ER stress pathways in ALD pathology. This study aimed to delineate the role of RAB25 in ALD and its regulatory mechanism in noncanonical ER stress pathways.</p><p><strong>Methods: </strong>RAB25 activation was examined in liver samples from ALD patients and ethanol-fed mice. The interaction between RAB25 and GCN1 was confirmed through mass spectrometry and co-immunoprecipitation (Co-IP) assays in vitro. The role of RAB25/GCN1 in promoting noncanonical ER stress in ALD was assessed both in vitro and in vivo.</p><p><strong>Results: </strong>RAB25 expression was upregulated and specifically accumulated on the endoplasmic reticulum in ALD. Mass spectrometry and Co-IP assays confirmed that RAB25 interacts with GCN1, thereby activating a noncanonical ER stress pathway that facilitates ALD progression. Further analysis revealed that RAB25 interaction with GCN1 inhibits K33-ubiquitination-mediated degradation of GCN1, promotes GCN2 phosphorylation, and subsequently activates ATF4-mediated ER stress. This activation modulates lipid metabolism, mitochondrial function, and inflammation, thereby facilitating ALD progression. Knockdown of RAB25 in hepatocytes inhibited ER stress activation and mitigated associated mitochondrial dysfunction, excessive lipid synthesis, and the exaggerated inflammatory response in an ALD model.</p><p><strong>Conclusions: </strong>Our findings demonstrate a causal role for RAB25-GCN1 signaling in activating the ER stress pathway, which contributes to ALD progression. This pathway may provide a proof-of-concept target for treating ALD and associated metabolic disorders.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":16.9,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013976","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}
{"title":"Correspondence to editorial on \"Dysfunction in CD8+ T Cells in Early-Stage HCC\" by Qin et al.: New Insights into HCC Immunotherapy.","authors":"Yang Kong, Xiaoqian Shen, Kun Xue, Haiying Wang","doi":"10.3350/cmh.2025.0880","DOIUrl":"https://doi.org/10.3350/cmh.2025.0880","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":16.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945145","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}
Pojsakorn Danpanichkul, Luis Antonio Diaz, Juan Pablo Arab, Amit G Singal, Ju Dong Yang
{"title":"Reply to Letter on \"Sex-Specific Trends and Demographic vs Epidemiologic Drivers of Alcohol-Related Cirrhosis in the U.S., 2021-2040\".","authors":"Pojsakorn Danpanichkul, Luis Antonio Diaz, Juan Pablo Arab, Amit G Singal, Ju Dong Yang","doi":"10.3350/cmh.2025.0948","DOIUrl":"https://doi.org/10.3350/cmh.2025.0948","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":16.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945169","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}
{"title":"Reply to Correspondence to \"Call for Preemptive Treatment of Cytomegalovirus in Patients with Cirrhosis and Acute Decompensation\".","authors":"Norihiro Imai","doi":"10.3350/cmh.2025.0963","DOIUrl":"https://doi.org/10.3350/cmh.2025.0963","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":16.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945097","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}
{"title":"SAFE Score in Chronic Liver Diseases: A Tool for Risk Enrichment and Personalized Surveillance.","authors":"Tung-Hung Su, Jia-Horng Kao","doi":"10.3350/cmh.2025.0940","DOIUrl":"https://doi.org/10.3350/cmh.2025.0940","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":16.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945113","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}
{"title":"Correspondence to the letter titled \"Beyond Diagnostic Accuracy: Economic and Clinical Considerations for NC-MRI in Late HCC Recurrence Surveillance\".","authors":"Dong Ho Lee","doi":"10.3350/cmh.2025.0945","DOIUrl":"https://doi.org/10.3350/cmh.2025.0945","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":16.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945112","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}
{"title":"An editorial on \"Human cytomegalovirus reactivation in cirrhosis patients with acute decompensation\" by Hong et al. Title: Human cytomegalovirus reactivation in decompensated cirrhosis: marker of immunosuppression or contributor to severity?","authors":"Zhujun Cao, Richard Moreau","doi":"10.3350/cmh.2025.0962","DOIUrl":"https://doi.org/10.3350/cmh.2025.0962","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":16.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945091","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}
{"title":"Sex‑Specific Trends and Demographic vs Epidemiologic Drivers of Alcohol‑Related Cirrhosis in United States, 2021-2040.","authors":"Kui Wang, Yunqing Zeng","doi":"10.3350/cmh.2025.0790","DOIUrl":"https://doi.org/10.3350/cmh.2025.0790","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":16.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945149","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}
{"title":"Correspondence to editorial on \"Human cytomegalovirus reactivation in cirrhosis patients with acute decompensation\".","authors":"Changze Hong, Jinjun Chen","doi":"10.3350/cmh.2025.0899","DOIUrl":"https://doi.org/10.3350/cmh.2025.0899","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":""},"PeriodicalIF":16.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945159","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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