Exercise-Mediated Regulation of Ferroptosis in Diabetic Cardiomyopathy: Mechanisms and Therapeutic Perspectives

Exercise is an important non-pharmacological intervention for the prevention and management of diabetes and its cardiovascular complications; however, the underlying mechanisms by which exercise confers cardiometabolic protection remain incompletely understood. Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes, characterized by progressive myocardial structural and functional abnormalities associated with oxidative stress, dysregulated lipid metabolism, chronic inflammation, and miochondrial dysfunction. Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a potential pathological link between metabolic disturbances and myocardial injury in DCM. Accumulating evidence suggests that exercise may modulate ferroptosis through multiple interconnected mechanisms, including restoration of iron homeostasis, suppression of lipid peroxidation, enhancement of endogenous antioxidant defenses, and improvement of mitochondrial function and quality control, thereby contributing to myocardial protection. In this review, we systematically summarize the cardioprotective benefits of exercise in the context of DCM and critically discuss the potential associations between exercise characteristics, including exercise modality, intensity, duration and the regulation of ferroptosis. By integrating current evidence on the molecular mechanisms underlying exercise-mediated ferroptosis regulation, this review provides a mechanistic framework for understanding how exercise may counteract ferroptosis in DCM and highlights the potential of ferroptosis-informed, precision exercise strategies for the prevention and management of diabetic cardiomyopathy.