Metabolic and Signaling Pathways of Macrophage Reprogramming in Atherosclerosis and Myocardial Infarction

Atherosclerosis and myocardial infarction remain the predominant contributors to mortality despite advances in interventional cardiology. Chronic inflammatory responses mediated by macrophages serve as a critical determinant of the pathogenesis of cardiovascular diseases. This review systematically dissects the immunometabolic and signaling networks underlying macrophage reprogramming, with a focus on key cardiovascular diseases. We assess the characteristics of M1 macrophages, which involve aerobic glycolysis, activation of the pentose phosphate pathway, and disruption of the tricarboxylic acid cycle, compared to M2 macrophages that rely on oxidative phosphorylation and fatty acid oxidation. Integrated signaling pathways dynamically regulate these metabolic programmes—centred on TLR/NF-κB-mediated inflammatory priming, JAK/STAT-dependent transcriptional polarization, and PI3K/Akt/mTOR-AMPK-PPARγ metabolic checkpoints, which interpret microenvironmental signals to control macrophage polarization. Within atherosclerotic lesions, we demonstrate that M1-dominant macrophage populations exacerbate plaque inflammation and compromise structural integrity, whereas M2 macrophages augment inflammatory resolution and tissue restoration. Following myocardial infarction, the timely therapeutic reprogramming from M1 to M2 phenotype is essential for efficiently attenuating adverse cardiac remodeling and improving cardiac function. Targeting metabolic enzymes and signaling pathways offers a promising strategy for reprogramming macrophages and mitigating cardiovascular diseases. Addresses species-specific differences in human vs murine immunometabolism. Emphasizes the context‑dependent roles of signaling pathways in macrophage polarization. Discusses the spatiotemporal dynamics of macrophage subsets in CVDs. Proposes precision macrophage reprogramming strategies with therapeutic timing.