The immune-cardiovascular metabolic circuitry in myocardial ischemia-reperfusion injury: from metabolic signal release to spatiotemporal reprogramming

Myocardial ischemia-reperfusion injury (MIRI) remains a major driver of infarct expansion, adverse remodeling, and poor outcomes after reperfusion therapy, yet mechanism-based treatments remain limited. Emerging evidence suggests that MIRI is not simply the additive result of oxidative stress and sterile inflammation. Rather, it reflects a spatiotemporally organized imbalance in immune–cardiac metabolic communication. In this framework, cardiomyocytes, coronary microvascular endothelial cells, fibroblasts, and resident cardiac macrophages act as both injury targets and signal-emitting units. They release succinate, lactate, ATP, lipid mediators, and mitochondrial danger signals. Infiltrating neutrophils, monocytes/macrophages, and lymphocyte subsets decode these cues through reprogramming of glycolysis, oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism. These responses shape inflammatory amplification, resolution, and tissue repair. This review summarizes key connecting mechanisms, including hypoxia sensing, mitochondrial dysfunction, and the axis linking adenosine monophosphate-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). It also discusses immunometabolites such as succinate, lactate, itaconate, and ATP/adenosine as links between tissue injury and immune cell-state transitions. Finally, we highlight temporal windows, spatial niches, and cell-state specificity, and evaluate how single-cell omics, spatial transcriptomics, spatial metabolomics, and metabolic flux analysis may guide time-sensitive, subpopulation-specific, and spatially precise therapies.