Pathogenesis of diabetic cardiomyopathy and emerging therapeutic strategies: a network-based perspective

Diabetic cardiomyopathy (DCM) is a distinct myocardial disease in diabetic patients, independent of coronary artery disease or hypertension, and a leading cause of heart failure. Its pathogenesis has evolved from a linear "glucolipotoxicity" model to a complex, dynamic network involving metabolic disturbances, mitochondrial dysfunction, oxidative stress, chronic inflammation, diverse programmed cell death pathways, cellular senescence, and cardiac autonomic neuropathy. These interconnected events are amplified through positive feedback loops, driving progressive myocardial damage. This review provides a systems-level synthesis of the networked pathogenesis of DCM, integrating evidence across core mechanistic components and their dynamic interactions. We discuss how metabolic disturbances initiate and propagate injury signals through mitochondrial dysfunction, inflammatory activation, and alterations in cardiomyocyte fate-including apoptosis, necroptosis, ferroptosis, and senescence. Distinct from prior reviews, this article explores two emerging integrative concepts: "metabolic-structural coupling"-abnormal physical interactions between metabolic molecules and myocardial structural proteins-and "metabolic memory"-epigenetically mediated persistence of injury despite glycemic control. We further provide a horizontal comparison and stage-specific assessment of emerging therapeutic strategies, including the pleiotropic network effects of SGLT2 inhibitors, the cardiovascular benefits of GLP-1 receptor agonists, targeting ferroptosis (e.g. irisin, alpha-lipoic acid), senolytics (e.g. dasatinib + quercetin), and the modulation of lipid droplet dynamics and the farnesoid X receptor (FXR). Finally, we critically evaluate the current evidence levels and translational barriers for these emerging therapies-from preclinical targets to completed randomized controlled trials-and propose a forward-looking roadmap to advance precision medicine in DCM. This roadmap emphasizes the multi-omics dissection of clinical heterogeneity, the development of mechanism-based biomarkers, and the validation of targeted combination therapies in well-designed clinical trials, with metabolic-structural coupling and metabolic memory serving as integrative links between classical pathways and disease persistence.