Metabolic regulation of macrophage polarization in myocardial infarction: from mechanisms to targeted therapies

BACKGROUND: Myocardial infarction (MI) elicits a tightly staged immune response in which macrophages coordinate early inflammation, subsequent tissue repair, and long-term ventricular remodeling. Growing evidence indicates that macrophage polarization is directed by immunometabolic reprogramming; however, the metabolic circuits that connect immune function to durable cardiac recovery remain incompletely defined. CONTENT: This review integrates current insights into the spatiotemporal, metabolic, and functional regulation of macrophages after MI. We summarize how glucose metabolism (glycolysis and the pentose phosphate pathway), TCA cycle rewiring and immunometabolic intermediates, lipid and amino-acid metabolism, iron handling and ferroptosis, purinergic and NAD⁺-dependent signaling, oxidative stress pathways, and vitamin-dependent regulation shape inflammatory versus reparative macrophage states. We highlight drug-targetable mediators-including lactate, succinate, α-KG, itaconate, kynurenine, and NAD⁺-linked pathways-and discuss how stage-specific targeting may suppress early injurious inflammation while promoting reparative remodeling. We also review advances in nanotechnology- and exosome-based delivery platforms that enable cardiac macrophage-directed interventions. OUTLOOK: Clinical translation will require deeper characterization of human macrophage heterogeneity, development of in vivo metabolic biomarkers, and validation in prospective multi-omics-anchored human studies. Temporally controlled combination therapies coupled with precision delivery systems may maximize cardiac repair while minimizing systemic metabolic toxicity. CONCLUSIONS: Macrophage immunometabolism is a central determinant of post-MI healing and remodeling. Therapeutic reprogramming of macrophage metabolism represents a promising precision-immunotherapy strategy to improve repair, limit heart failure progression, and expand future cardiovascular treatment options. CLINICAL TRIAL NUMBER: Not applicable.