Abstract

Diabetic cardiomyopathy (DCM) is a major contributor to heart failure in patients with diabetes and is driven by progressive cardiomyocyte loss, chronic inflammation, metabolic dysregulation, and adverse myocardial remodeling. Accumulating evidence indicates that cardiomyocyte death in DCM results from the coordinated activation of multiple regulated cell death programs rather than a single dominant pathway. Beyond apoptosis, non-apoptotic modalities including pyroptosis, necroptosis, ferroptosis, and the recently described cuproptosis have emerged as critical contributors to diabetic myocardial injury. These death programs converge and interact through shared upstream stressors, most prominently oxidative stress, mitochondrial dysfunction, metabolic imbalance, and inflammatory signaling, which amplify myocardial damage and promote disease progression. Central molecular hubs such as receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL), the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, AMP-activated protein kinase (AMPK)–nuclear factor erythroid 2–related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) antioxidant signaling, and mitochondrial quality-control pathways coordinate crosstalk among apoptotic and non-apoptotic cell death modalities. Recent evidence further supports the existence of integrated cell death phenotypes such as PANoptosis (pyroptosis–apoptosis–necroptosis), highlighting the dynamic and interconnected nature of cell fate decisions in the diabetic heart. This review synthesizes current mechanistic insights into regulated cell death networks in DCM, emphasizing convergence points, pathway crosstalk, and emerging metal-dependent mechanisms such as cuproptosis. Here, we propose a conceptual framework that may facilitate the identification of shared therapeutic targets to more effectively limit cardiomyocyte loss and attenuate disease progression.