Abstract
Effective tissue repair after acute myocardial infarction (MI) critically depends on the timely and orderly resolution of inflammation. This review systematically elaborates the core "directorial" role of efferocytosis-the immunologically silent clearance of apoptotic cells-which orchestrates the post-MI immune microenvironment from inflammation to repair through precise spatiotemporal regulation. We dissect its complete molecular program, from "find-me/eat-me" signals and TAM-TIM receptor synergy to metabolic-transcriptional reprogramming that drives repair. A key focus is how efferocytic dysfunction (e.g., MerTK cleavage, CD47 upregulation, Lgmn blockade) triggers a self-perpetuating vicious cycle of failed clearance, sustained inflammation, and repair collapse, leading to adverse remodeling and heart failure. Critically, we highlight the context-dependent duality of key molecules, emphasizing that therapeutic success requires restoring physiological balance rather than maximal pathway activation. Building on this mechanistic understanding, we review multi-dimensional strategies-disabling "don't-eat-me" signals, enhancing degradation capacity, and reprogramming the immune microenvironment-while critically analyzing translational challenges. Finally, we envision a paradigm shift toward spatially targeted, temporally precise interventions that actively guide repair, laying a theoretical foundation for innovative efferocytosis-directed therapies.