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Cardiotoxicity is a common side effect of cisplatin in cancer treatment, often complicating patient care. Tangeretin (TG), a natural compound found in citrus peel, shows promise in protecting against cisplatin-induced heart damage. Our study investigated TG’s protective effects both in cell culture and in animal models. TG effectively countered cisplatin-induced damage in heart cells, promoting mitochondrial health and glucose transporter expression. In animal studies, TG reduced markers of heart damage and improved cardiac function. Mechanistically, TG activated AMPK, reduced the inactivation of Acetyl-CoA Carboxylase (ACC) protein and inhibited p38 MAPK and prevented mitochondrial dysfunction and cell death. This research sheds light on TG’s potential in safeguarding the heart from cisplatin-induced harm.