Macrophage Metabolic Reprogramming and Its Role in Heart Diseases

Cardiovascular diseases, particularly heart failure, remain the leading cause of death. Pathological cardiac remodeling, driven by chronic inflammation and metabolic dysfunction, is a key underlying mechanism. Macrophages, central regulators of cardiac inflammation, exhibit remarkable functional plasticity shaped by metabolic reprogramming. This review synthesizes current evidence on how metabolic shifts—glycolysis, fatty acid oxidation, and amino acid metabolism—dictate macrophage phenotypes in ischemic and non-ischemic heart diseases. In myocardial infarction, hypoxia-induced glycolytic reprogramming fuels pro-inflammatory CCR2⁺ macrophages, while oxidative metabolism supports reparative subsets. In non-ischemic conditions like HFpEF, metabolic stress from obesity or diabetes skews macrophages toward a dysfunctional, pro-fibrotic state. Key regulatory pathways (e.g., HIF-1α, PPARγ, AMPK) and metabolite-driven epigenetic modifications (e.g., lactylation, succinylation) further link metabolism to macrophage-mediated remodeling. Therapeutic strategies targeting glycolysis (e.g., PFKFB3 inhibition) or promoting oxidative metabolism (e.g., PPARγ agonists) show preclinical promise but face challenge in specificity. Future directions emphasize spatial-temporal mapping of macrophage metabolism and precision-targeted interventions to resolve inflammation and restore cardiac homeostasis.