Regulated cell death programs in the pathogenesis of diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is a major cause of heart failure in patients with diabetes and arises from chronic metabolic stress, oxidative injury, inflammation, microvascular dysfunction, and adverse myocardial remodeling. Although apoptosis has long been considered the dominant form of cardiomyocyte death in DCM, accumulating evidence indicates that diabetic myocardial injury involves a broader network of regulated cell death (RCD) programs. This review integrates current evidence on apoptosis, pyroptosis, necroptosis, ferroptosis, cuproptosis, and PANoptosis in DCM, emphasizing their upstream diabetic triggers and molecular convergence nodes. Hyperglycemia, lipotoxicity, advanced glycation end products, mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, iron-dependent lipid peroxidation, iron and copper dyshomeostasis, all activate overlapping rather than isolated cell death pathways. Mitochondrial ROS production, intracellular calcium imbalance, maladaptive unfolded protein response signaling, NLRP3 inflammasome activation, antioxidant failure, impaired mitochondrial quality control, and metal-dependent mitochondrial vulnerability emerge as central hubs connecting these programs. Importantly, RCD in DCM affects not only cardiomyocytes but also cardiac microvascular endothelial cells, fibroblasts, and immune cells, thereby linking cell death to capillary rarefaction, sterile inflammation, extracellular matrix remodeling, and fibrosis. We propose that RCD in DCM should be viewed as a dynamic, disease-stage-dependent network in which early metabolic injury favors mitochondrial apoptosis, persistent inflammation promotes pyroptosis and necroptosis, redox-lipid imbalance facilitates ferroptosis, and metal-dependent mitochondrial stress may contribute to emerging death phenotypes. This integrated framework may help identify shared upstream therapeutic targets capable of limiting myocardial injury more effectively than strategies focused on single terminal death pathways.