Efferocytosis in myocardial infarction: the regulatory core from inflammation resolution to cardiac repair

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.