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. AGEs accumulate in cardiomyocytes under diabetic conditions, impairing mitochondrial antioxidant defense through the RAGE-Nrf2-SOD2 axis. Upon myocardial ischemia/reperfusion insult, diabetic cardiomyocytes exhibit heightened susceptibility to mitochondrial oxidative damage, which in turn triggers the assembly of the AIM2-ZBP1 PANoptosome and ultimately activates PANoptosis. • Advanced glycation end-products (AGEs) accumulate in myocardium and exacerbate myocardial ischemia/reperfusion injury (MI/RI) in diabetic animal model. • AGEs trigger PANoptosis in cardiomyocytes via activation of the AIM2-ZBP1 PANoptosome and upregulation of multiple cell death executors (cleaved caspase-3, GSDMD, p-MLKL). • AGEs, via their receptor RAGE, suppress the master antioxidant transcription factor Nrf2, leading to downregulation of mitochondrial superoxide dismutase 2 (SOD2). This axis is the key to impaired mitochondrial antioxidant defense in diabetic cardiomyocytes. • Targeting the AGEs-mitochondrial oxidative stress-PANoptosis axis represents a promising and clinically translatable strategy for diabetic cardiovascular complications. • Combination therapy with pyridoxamine (AGE inhibitor) and empagliflozin (SGLT2 inhibitor) potently inhibits AGEs formation and attenuates MI/RI in diabetic mice.