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Here, the role of alnustone is explored, a natural compound derived from the traditional Chinese herb <jats:italic>Alpinia katsumadai<\/jats:italic> Hayata, in the treatment of MASLD and MASH. It is shown that alnustone administration potently reduces serum triacylglycerol levels, reverses liver steatosis, and alleviates\u00a0insulin resistance in both male and female MASLD mice. It also effectively ameliorates established fibrosis in MASH mice without any side effects. Mechanistically, hepatic lipidome profiling and energy metabolic assays reveal that alnustone facilitates mitochondrial fatty acid \u03b2\u2010oxidation. Employing limited proteolysis\u2010mass spectrometry (LiP\u2010SMap) and further validation, calmodulin is identified as a direct molecular target of alnustone. Alnustone interacts with the Ca<jats:sup>2+<\/jats:sup>\u2010binding site of calmodulin, leading to increased cytosolic and mitochondrial Ca<jats:sup>2+<\/jats:sup> levels and enhanced mitochondrial function, whereas liver\u2010specific calmodulin knockdown abrogates alnustone's therapeutic effects. Moreover, calmodulin is downregulated in human livers of patients with MASLD and MASH, and is genetically associated with reduced MASLD risk. These findings establish alnustone as a promising natural compound and highlight calmodulin as a target for treating MASLD.<\/jats:p>","DOI":"10.1002\/advs.202411984","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T08:57:46Z","timestamp":1749113866000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Alnustone Ameliorates Metabolic Dysfunction\u2010Associated Steatotic Liver Disease by Facilitating Mitochondrial Fatty Acid \u03b2\u2010Oxidation via Targeting Calmodulin"],"prefix":"10.1002","volume":"12","author":[{"given":"Shourui","family":"Hu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health Center for Reproductive Medicine Institute of Women Children and Reproductive Health Shandong University  Jinan Shandong 250012 China"},{"name":"National Research Center for Assisted Reproductive Technology and Reproductive 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