Atherosclerosis is the leading cause of cardiovascular morbidity and mortality worldwide, driven not only by lipid accumulation but also by chronic inflammation and defective tissue repair. Among immune cells within plaques, macrophages orchestrate both inflammatory injury and reparative responses, and their fate is critically regulated by mitochondrial quality control. Damaged mitochondria release mitochondrial reactive oxygen species and mitochondrial DNA, which activate innate immune pathways, such as the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome and the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, thereby amplifying inflammation. Mitophagy, the selective clearance of dysfunctional mitochondria, has emerged as a metabolic checkpoint determining whether macrophages sustain inflammation or transition toward repair. Key signaling axes, including phosphatase and tensin homolog (PTEN)-induced kinase 1/Parkin, BNIP3 (BCL2/adenovirus E1B 19-kDa interacting protein 3)/NIX (NIP3-like protein X), and FUNDC1 (FUN14 domain-containing protein 1), converge to limit mitochondrial reactive oxygen species and mitochondrial DNA release, suppress innate immune activation, and preserve oxidative metabolism. By maintaining energy balance, mitophagy supports efferocytosis, extracellular matrix deposition, and fibrous cap stabilization, whereas its impairment drives necrotic core expansion and plaque vulnerability. Preclinical studies demonstrate that mitophagy can be therapeutically modulated by small molecules (metformin and resveratrol), natural products (salidroside), gene-based and nanoparticle approaches, and lifestyle interventions. This review summarizes mechanistic insights into macrophage mitophagy, emphasizes its role as a metabolic checkpoint in the inflammation-to-repair transition, and discusses translational opportunities and challenges in targeting this pathway to stabilize vulnerable plaques.
