Decoding metabolism-driven cell death switching in myocardial ischemia-reperfusion injury: From mechanistic networks...

Myocardial ischemia-reperfusion injury (MIRI) remains a major barrier to the full benefit of reperfusion therapy for acute myocardial infarction. Rather than reflecting activation of a single death pathway, MIRI is shaped by abrupt metabolic shifts after blood-flow restoration that alter the susceptibility and relative contribution of multiple regulated cell-death programs, including ferroptosis, pyroptosis, necroptosis, apoptosis, autophagy-associated injury, and mitochondrial permeability transition pore-dependent necrosis. This Review synthesizes how ATP depletion, lactate accumulation, mitochondrial redox imbalance, calcium overload, iron dyshomeostasis, lipid peroxidation, impaired glutathione-GPX4 buffering, and inflammatory priming jointly shape death-state susceptibility. Here, "metabolism-driven cell-death switching" is used operationally to denote a metabolically induced change in the relative probability or dominance of death states across cells, regions, or reperfusion phases; direct longitudinal demonstration of terminal fate conversion within the same cell remains limited. We further examine how diabetes, obesity, dyslipidaemia, ageing, and endothelial dysfunction remodel the myocardial metabolic environment and generate cell-type-specific vulnerabilities. Therapeutic evidence is integrated across natural products, small-molecule drugs, endogenous metabolites, extracellular vesicles, engineered nanomaterials, and targeted delivery systems, with emphasis on intervention timing, cell-type specificity, disease modelling, and clinical translation. By framing regulated cell death as metabolism-gated and context dependent, this Review proposes an evidence-graded, testable framework for death-state-guided stratification, rational combination therapy, and precision cardioprotection in MIRI.