Lipid metabolic reprogramming in myocardial ischaemia/reperfusion injury: mechanisms and therapeutic opportunities

Myocardial ischaemia/reperfusion injury limits myocardial salvage after acute coronary occlusion. Although reperfusion is essential, the return of oxygen and substrates also exposes previously ischaemic myocardium to abrupt oxidative, ionic, microvascular, and inflammatory stress. Lipid handling is increasingly recognised as one important setting in which these stresses intersect. The strength of evidence, however, is not uniform across human lipidomics, animal models, cellular systems, and intervention studies. During ischaemia and reperfusion, fatty acid uptake, mitochondrial fatty acid oxidation, acylcarnitine handling, cardiolipin remodelling, sphingolipid signalling, polyunsaturated fatty acid-phospholipid peroxidation, and lipid droplet buffering may become temporally uncoupled. These changes may contribute to mitochondrial dysfunction, membrane lipid injury, ferroptosis-related susceptibility, endothelial impairment, and immune-metabolic remodelling. In this review, we synthesise mechanistic, preclinical, and early human lipidomic evidence and propose a temporal-multicellular lipid injury model in which lipid remodelling may amplify canonical myocardial reperfusion-injury mechanisms, including substrate mismatch, reactive oxygen species generation, Ca2 + overload, mitochondrial permeability transition pore susceptibility, inflammation, and repair-phase remodelling. We distinguish biomarker associations from experimentally supported causal mechanisms and discuss how lipid-directed strategies could be developed as phase-specific, cell-aware, and biomarker-guided cardioprotection. The field remains clinically immature: most interventions are preclinical, spatial and cell-type resolution remains limited, and no lipid-centred therapy is currently established as an adjunct to reperfusion in ST-segment elevation myocardial infarction.