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Recent studies have highlighted the role of calpain, a calcium\u2010dependent protease, in liver inflammation and fibrosis. Calpain activity is regulated by its essential subunit, Capns1 (calpain\u20104), which stabilizes and modulates the activity of its catalytic isoforms, calpain\u20101 and calpain\u20102. This study investigated calpain's impact on lipid metabolism in ALD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Six\u2010week\u2010old C57Bl6\/J mice were injected with rAAV8 vectors encoding Capns1 shRNA or control vectors. After 4\u2009weeks, mice underwent a 10\u2010day period of ad\u00a0libitum ethanol consumption, followed by a single gavaged ethanol administration on day 11.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Capns1 knockdown attenuated ethanol\u2010induced microvesicular steatosis. Hepatic triglyceride and free fatty acid levels were not significantly altered, whereas cholesterol levels were significantly reduced in the ethanol group with Capns1 knockdown.\n                      <jats:italic>Cpt1a<\/jats:italic>\n                      expression increased significantly in the ethanol group with Capns1 knockdown. Western blot analysis revealed increased Cleaved\u20103\u2010hydroxy\u20103\u2010methyl\u2010glutaryl\u2010coenzyme A reductase (HMGCR) to Pro\u2010HMGCR ratio in Capns1\u2010knockdown mice, suggesting reduced HMGCR activity and suppressed cholesterol biosynthesis. LXR\u03b1 expression was mainly increased in the cytoplasm in the ethanol group, and following Capns1 knockdown, it was relocalized to the nucleus via its activation. In addition, RNA sequencing analysis indicated that Capns1 knockdown contributes to the reprogramming of ethanol\u2010induced disruptions in metabolic pathways, primarily those involving cholesterol metabolism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Further investigation into the relationship between Capns1 and cholesterol biosynthesis proteins may provide insights into using calpain inhibitors as a therapeutic approach for alcohol\u2010related liver disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/acer.70356","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T11:16:03Z","timestamp":1781694963000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Calpain\u20104 Knockdown Modulates Cholesterol Metabolism and\n                    <scp>LXR\u03b1<\/scp>\n                    Nuclear Localization in Experimental Alcohol\u2010Related Liver Disease"],"prefix":"10.1111","volume":"50","author":[{"given":"Noriko","family":"Kitano","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4812-2501","authenticated-orcid":false,"given":"Jiang","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Taborski","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine University of Pittsburgh  Pittsburgh Pennsylvania 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