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Lipophagy has been shown to be involved in the maintenance of LDs homeostasis. The objective of this study was to explore the mechanism of lipophagy in cardiomyocytes and investigate whether berberine could mitigate DCM by modulating this pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Bioinformatics analysis identified disorders of lipid metabolism and autophagy in DCM. To carry out further research, db\/db mice were utilized. Furthermore, H9C2 cells treated with palmitic acid were employed as a model to explore the molecular mechanisms involved in myocardial lipotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The results showed that lipophagy was impaired in DCM. Mechanistically, sirtuin 3 (SIRT3) was demonstrated to regulate lipophagy in cardiomyocytes. SIRT3 was down\u2010regulated in DCM. Conversely, activation of SIRT3 by the activator nicotinamide riboside (NR) could promote lipophagy to alleviate PA\u2010induced lipotoxicity in H9C2 cells. Moreover, berberine administration markedly mitigated diabetes\u2010induced cardiac dysfunction and hypertrophy in db\/db mice, which dependent on SIRT3\u2010mediated lipophagy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Collectively, SIRT3 could moderate cardiac lipotoxicity in DCM by promoting lipophagy, suggesting that the regulation of SIRT3\u2010mediated lipophagy may be a promising strategy for treating DCM. The findings indicate that the therapeutic potential of berberine for DCM is associated with lipophagy.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.20\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.20\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70035","type":"journal-article","created":{"date-parts":[[2025,4,13]],"date-time":"2025-04-13T20:42:16Z","timestamp":1744576936000},"page":"5038-5056","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Berberine partially ameliorates cardiolipotoxicity in diabetic cardiomyopathy by modulating SIRT3\u2010mediated lipophagy to remodel lipid droplets homeostasis"],"prefix":"10.1111","volume":"182","author":[{"given":"Wenxian","family":"Chen","sequence":"first","affiliation":[{"name":"Zhuhai People's Hospital, Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai 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