{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:04:55Z","timestamp":1783919095554,"version":"3.55.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"\n Background &amp; aims<\/jats:title>\n \n The pathogenesis of alcohol-associated liver fibrosis remains incompletely understood. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme responsible for detoxifying ethanol-derived acetaldehyde. Notably, the\n ALDH2<\/jats:italic>\n rs671 variant is carried by approximately 8% of the global population, with a prevalence of 30%\u201350% in East Asians. This variant reduces ALDH2 enzymatic activity. However, the contribution of impaired ALDH2 function to fibrotic susceptibility and the underlying regulatory molecules remains to be fully elucidated.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Blood samples from patients with alcohol-associated liver disease (ALD) were collected for\n ALDH2<\/jats:italic>\n rs671 genotyping, with concurrent assessment of liver stiffness. Global\n Aldh2<\/jats:italic>\n knockout (\n \n Aldh2\n -\/<\/jats:sup>\n <\/jats:italic>\n -<\/jats:sup>\n ) and wild-type (WT) mice were treated with ethanol or carbon tetrachloride (CCl\n 4<\/jats:sub>\n ) or a combination of both.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 80 patients with ALD, those carrying the\n ALDH2<\/jats:italic>\n rs671 variant (n = 34) exhibited comparable liver fibrosis-related indices to\n ALDH2<\/jats:italic>\n wild-type patients (n = 46) despite significantly lower cumulative alcohol intake. Compared with WT mice,\n \n Aldh2\n -\/<\/jats:sup>\n <\/jats:italic>\n -<\/jats:sup>\n mice treated with ethanol and CCl\n 4<\/jats:sub>\n showed exacerbated hepatic fibrosis, with transcriptomic analysis revealing predominant enrichment of differentially expressed genes in mitochondrial pathways, accompanied by reduced hepatic mitochondrial size and redox imbalance. Acyl-CoA synthetase long-chain family member 1 (ACSL1) was identified as a candidate molecule associated with fibrotic progression under ALDH2-deficient conditions. ACSL1 expression was downregulated in liver tissue from ethanol plus CCl\n 4<\/jats:sub>\n -treated\n \n Aldh2\n -\/<\/jats:sup>\n <\/jats:italic>\n -<\/jats:sup>\n mice, coinciding with elevated hepatic long-chain free fatty acids.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n This study suggests a potential clinical association between the\n ALDH2<\/jats:italic>\n rs671 variant and increased fibrosis susceptibility in patients with ALD, and identifies ACSL1 as a candidate molecule associated with alcohol-associated fibrotic progression under ALDH2-deficient conditions, providing a basis for future mechanistic studies.\n <\/jats:p>\n <\/jats:sec>\n \n Impact and implications<\/jats:title>\n \n This study provides clinical evidence suggesting a potential association between the prevalent\n ALDH2<\/jats:italic>\n rs671 variant and increased susceptibility to alcohol-associated liver fibrosis. Mitochondrial alterations may contribute to fibrotic progression in\n Aldh2<\/jats:italic>\n -deficient mice exposed to ethanol and CCl\n 4<\/jats:sub>\n . ACSL1 was identified as a candidate molecule associated with this process. These findings extend the current understanding of mitochondrial and metabolic alterations involved in ALDH2-related alcohol-associated fibrotic injury and provide a basis for future mechanistic studies.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fphys.2026.1873663","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T04:23:52Z","timestamp":1783916632000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of mitochondria-associated hub genes related to alcohol-associated liver fibrosis progression in aldehyde dehydrogenase 2 deficiency"],"prefix":"10.3389","volume":"17","author":[{"given":"Feiyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University","place":["Changchun, China"]},{"name":"Jilin Provincial Key Laboratory of Metabolic Liver Diseases, The First Hospital of Jilin University, Jilin University","place":["Changchun, China"]},{"name":"China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, The First Hospital of Jilin University, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University","place":["Changchun, China"]},{"name":"Jilin Provincial Key Laboratory of Metabolic Liver Diseases, The First Hospital of Jilin University, Jilin University","place":["Changchun, China"]},{"name":"China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, The First Hospital of Jilin University, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2362","DOI":"10.1038\/s41467-020-16092-0","article-title":"Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis","volume":"11","author":"An","year":"2020","journal-title":"Nat. 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