The role of macrophage autophagy and mitochondrial metabolic reprogramming in the treatment of myocardial infarction

Myocardial infarction (MI) is a life-threatening cardiovascular event, and preventing subsequent heart failure remains a major clinical challenge despite available treatments. The repair outcome critically depends on the cardiac immune microenvironment, where macrophages play a pivotal role. Their functional switch from pro-inflammatory to reparative phenotypes is driven by mitochondrial metabolic reprogramming, a process regulated by autophagy, particularly mitophagy. However, the integrated role of the macrophage autophagy-metabolism axis in post-MI repair is not fully systematized. This review comprehensively examines the interplay between macrophage autophagy and mitochondrial metabolic reprogramming. It details how mitophagy maintains mitochondrial fitness to suppress inflammation and fuel the oxidative metabolism essential for reparative macrophage function. The discussion extends to advanced regulatory mechanisms, including inter-organelle communication, mechanosensing, and intercellular mitochondrial transfer. Furthermore, the review evaluates emerging therapeutic strategies, such as precision nanomedicine and multi-target interventions, within complex clinical contexts like diabetic MI. Key challenges, including the spatiotemporal complexity of macrophage dynamics and translational bottlenecks, are also addressed. By synthesizing current insights, this review establishes a novel immunometabolic framework centered on the macrophage autophagy-metabolism axis. It highlights that targeting this axis holds significant therapeutic potential for optimizing cardiac repair. The review provides forward-looking perspectives, emphasizing the need for intelligent, spatiotemporally precise therapeutic platforms to advance the development of targeted therapies for MI. Elucidates how macrophage mitophagy orchestrates immunometabolic switching between inflammatory and reparative phenotypes post-myocardial infarction, offering novel therapeutic targets. Explores novel regulatory dimensions including inter-organelle communication and mechanobiology, providing fresh perspectives on microenvironmental control of macrophage function. Evaluates cutting-edge therapeutic strategies like precision nanomedicine and multi-target interventions, highlighting translational potential in complex clinical scenarios. Synthesizes the macrophage autophagy-metabolism axis as an integrated framework, paving the way for next-generation cardiac repair therapies.