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Nobiletin, a polymethoxyflavone abundant in citrus fruits, enhances circadian rhythms and ameliorates diet\u2010induced hepatic steatosis, but its influences on ALD are unknown. This study investigates the role of brain and muscle Arnt\u2010like protein\u20101 (<jats:italic>Bmal1<\/jats:italic>), a key regulator of the circadian clock, in nobiletin\u2010alleviated ALD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>This study uses chronic ethanol feeding plus an ethanol binge to establish ALD models in <jats:italic>Bmal1<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> and <jats:italic>Bmal1<\/jats:italic> liver\u2010specific knockout (<jats:italic>Bmal1<\/jats:italic>LKO) mice. Nobiletin mitigates ethanol\u2010induced liver injury (alanine aminotransferase [ALT]), glucose intolerance, hepatic apoptosis, and lipid deposition (triglyceride [TG], total cholesterol [TC]) in <jats:italic>Bmal1<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> mice. Nobiletin fails to modulated liver injury (ALT, aspartate aminotransferase [AST]), apoptosis, and TG accumulation in <jats:italic>Bmal1<\/jats:italic>LKO mice. The expression of lipogenic genes (acetyl\u2010CoA carboxylase alpha [<jats:italic>Acaca<\/jats:italic>], fatty acid synthase [<jats:italic>Fasn<\/jats:italic>]) and fatty acid oxidative genes (carnitine pamitoyltransferase [<jats:italic>Cpt1a<\/jats:italic>], cytochrome P450, family 4, subfamily a, polypeptide 10 [<jats:italic>Cyp4a10<\/jats:italic>], and cytochrome P450, family4, subfamily a, polypeptide 14 [<jats:italic>Cyp4a14<\/jats:italic>]) is inhibited, and\u00a0the expression of proapoptotic genes (Bcl2 inteacting mediator of cell death [<jats:italic>Bim<\/jats:italic>]) is enhanced by ethanol in <jats:italic>Bmal1<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> mice. Nobiletin antagonizes the expression of these genes in <jats:italic>Bmal1<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> mice and not in <jats:italic>Bmal1<\/jats:italic>LKO mice. Nobiletin activates protein kinase B (PKB, also known as AKT)\u00a0phosphorylation, increases the levels of the carbohydrate response element binding protein (ChREBP), ACC1, and FASN, and reduces the level of sterol\u2010regulatory element binding protein 1 (SREBP1)\u00a0and phosphorylation of ACC1 in a <jats:italic>Bmal1<\/jats:italic>\u2010dependent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Nobiletin alleviates ALD by increasing the expression of genes involved in fatty acid oxidation by increasing AKT phosphorylation and lipogenesis in a <jats:italic>Bmal1<\/jats:italic>\u2010dependent manner.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.202300833","type":"journal-article","created":{"date-parts":[[2024,6,8]],"date-time":"2024-06-08T11:00:34Z","timestamp":1717844434000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Nobiletin Protects Against Alcoholic Liver Disease in Mice via the BMAL1\u2010AKT\u2010Lipogenesis Pathway"],"prefix":"10.1002","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2392-1227","authenticated-orcid":false,"given":"Xudong","family":"Li","sequence":"first","affiliation":[{"name":"Food Safety and Health Research Center School of Public Health Southern Medical University  Guangzhou Guangdong 510515 China"},{"name":"Department of Toxicological and Biochemical Test Guangzhou Center for Disease Control and Prevention  Guangzhou Guangdong 510440 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runxuan","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Food Safety and Health Research Center School of Public Health Southern Medical University  Guangzhou Guangdong 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[{"name":"Food Safety and Health Research Center School of Public Health Southern 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