Advanced glycation end-products exacerbate myocardial ischemia/reperfusion injury by promoting mitochondrial oxidative damage and PANoptosis in diabetes mellitus.

Diabetes mellitus exacerbates myocardial ischemia/reperfusion injury (MI/RI), but the underlying mechanisms remain unclear. The present study identifies advanced glycation end-products (AGEs) as a key pathological mediator. Upon hypoxia/reoxygenation (H/R) stimulation, AGEs-primed cardiomyocytes exhibited drastic mitochondrial oxidative damage, characterized by elevated mitochondrial reactive oxygen species (mtROS), loss of mitochondrial membrane potential, depletion of ATP, and increased release of mitochondrial DNA and cytochrome c. Mechanistically, AGEs impaired the mitochondrial antioxidant defense via the RAGE-Nrf2-SOD2 axis. Furthermore, AGEs activated the AIM2-ZBP1 PANoptosome, triggering PANoptosis characterized by concurrent upregulation of cleaved caspase-3, GSDMD, and p-MLKL. Mitochondrial oxidative damage was established as the causal upstream event, as a mitochondria-targeted antioxidant or RAGE silencing attenuated PANoptosis, while mtROS inducer (antimycin A) directly activated PANoptosis. Therapeutically, combination treatment with pyridoxamine (an AGEs inhibitor) and empagliflozin (an SGLT2 inhibitor) in diabetic mice potently suppressed AGEs accumulation, mitigated mitochondrial damage and PANoptosis, and significantly improved cardiac recovery post-MI/R. Thus, targeting the AGEs-mitochondrial damage-PANoptosis axis via combined pyridoxamine and empagliflozin represents a promising strategy to alleviate diabetic MI/RI.