Shikonin attenuates doxorubicin-induced myocardial senescence and fibrosis in association with improved redox and mitochondrial homeostasis.

objectiveDoxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent; however, its cumulative cardiotoxicity limits its clinical use. Oxidative stress, mitochondrial dysfunction, myocardial senescence, and fibrotic remodeling contribute to chronic DOX-induced cardiac injury. Shikonin (SKN), a natural naphthoquinone compound, possesses antioxidant and mitochondrial protective properties. However, whether SKN can attenuate DOX-induced myocardial senescence and fibrosis remains unclear. METHODS AND

resultsA chronic DOX-induced cardiotoxicity model was established in male Sprague- Dawley rats, followed by treatment with SKN or captopril. Cardiac function, myocardial injury and fibrosis, oxidative stress, mitochondrial dysfunction, and senescence-associated changes were assessed using echocardiography, histological and fluorescence staining, biochemical assays, and Western blotting. Complementary DRP1 loss- and gain-of-function experiments were performed in DOX-treated H9c2 cardiomyoblasts. DOX impaired cardiac function, disrupted myocardial structure, increased collagen deposition, induced redox imbalance and mitochondrial membrane depolarization, and promoted myocardial senescence. SKN ameliorated these alterations and reduced DRP1, FIS1, P-p53, and p21 expression. In H9c2 cells, DRP1 knockdown mimicked several protective effects of SKN, whereas DRP1 overexpression partially reversed its effects on mitochondrial superoxide accumulation and senescence-associated changes.

conclusionSKN attenuates DOX-induced myocardial injury, senescence, and fibrosis. These effects are associated with improved redox and mitochondrial homeostasis and suppression of p53/p21-associated senescence signaling, with DRP1-related mitochondrial dysregulation contributing to the protective effects of SKN.