Melatonin Attenuates Glucolipotoxicity-Induced Cardiac Oxidative Stress, Inflammation, Pyroptosis, and Fibrotic Remodeling in STZ/HFD-Treated ApoE−/− Mice

Diabetic cardiomyopathy (DCM) under glucolipotoxic stress is sustained by a reactive oxygen species (ROS)-driven circuit in which oxidative DNA damage and nitrosative injury prime NLR family pyrin domain containing 3 (NLRP3) inflammasome assembly, triggering caspase-1 activation, gasdermin D (GSDMD) cleavage, and pyroptotic cardiomyocyte death that propagates apoptosis and fibrotic remodeling. Whether melatonin can disrupt this oxidative-pyroptotic axis when both hyperglycemia and dyslipidemia coexist, the metabolic context most refractory to current therapy has not been established. Apolipoprotein E-deficient (ApoE−/−) mice were subjected to streptozotocin-induced hyperglycemia and high-fat diet-induced dyslipidemia, then treated with oral melatonin (20 mg/kg/day) for 8 weeks. Despite unchanged fasting glycemia, melatonin attenuated cardiac oxidative stress, reducing 8-OHdG and inducible nitric oxide synthase while restoring Nrf2. Suppression of nuclear factor-κB and NLRP3 was accompanied by lowered interleukin-1β, caspase-1, and GSDMD, indicating disrupted inflammasome priming and pyroptotic execution. Downstream pathology was concurrently attenuated, with reduced TUNEL-positive cardiomyocytes, normalized Bax/Bcl-2 ratio, lower natriuretic peptide expression, diminished interstitial fibrosis, and improved electrocardiographic parameters. These findings position melatonin as a cardioprotective agent that operates despite persistent fasting hyperglycemia, acting through combined attenuation of lipid burden, cumulative glycemic stress, oxidative stress, and inflammatory signaling to arrest downstream apoptotic and fibrotic remodeling under glucolipotoxic conditions, providing a mechanistic rationale for adjunctive melatonin therapy in DCM.