Cellular Senescence in Diabetic Cardiomyopathy: Mechanistic Insights and Therapeutic Perspectives

Diabetic cardiomyopathyis a distinct cardiac disorder marked by diabetes-associated myocardial structural and functional abnormalities, developing independently of other overt cardiovascular diseases. Mounting evidence suggests that cellularsenescence serves as a central mechanism, linking metabolic stress to mitochondrial dysfunction, chronic inflammation, and adverse cardiac remodeling. In the diabetic heart, senescence manifests as sustained cell-cycle arrest, impaired mitochondrial function, and a proinflammatory senescence-associated secretory phenotype (SASP). These features collectively drive detrimental structural and functional remodeling. Mechanistically, this process involves defective mitochondrial quality control, influenced by regulators such as Sirtuin 3 (SIRT3) and ATP synthase O subunit (ATP5O). Furthermore, aberrant activation of signaling pathways, including p53, FOXO1-Angiopoietin-like 4 (ANGPTL4), and various miRNA-dependent mechanisms, drives senescence in both cardiomyocytes and cardiac progenitor cells under diabetic conditions. Epigenetic remodeling and RNA methylation further shape this process by influencing transcriptional regulation and proteostasis. Concurrently, immunoinflammatory crosstalk, particularly macrophage polarization and persistent SASP-mediated inflammation, exacerbates myocardial fibrosis and dysfunction. It is notable that type 1 and type 2 diabetes present distinct patterns of senescence burden, mitochondrial impairment, and cardiac phenotypes.Promising therapeutic strategies targeting senescence-associated pathways, including senolytics, metabolic modulators, mitochondrial protectants, and epigenetic regulators, have demonstrated potential in preclinical and emerging clinical studies. This review integrates current insights into the complex interplay among metabolic stress, mitochondrial injury, and cellular senescence in Diabetic cardiomyopathy. It also highlights promising directions for mechanism-based interventions aimed at combating diabetic cardiac remodeling.