More Than a Cleanup Crew: The Expanding Biology of Efferocytosis

Efferocytosis, the process by which phagocytes clear apoptotic cells, is essential for tissue homeostasis, inflammation resolution, and repair. Once considered a passive waste-disposal process, efferocytosis is now recognized as a dynamic, immunometabolic program that integrates apoptotic cell clearance with metabolic reprogramming and inflammation resolution. In cardiovascular contexts, efficient efferocytosis limits necrosis, enhances the deposition of wound healing matrix proteins, and promotes tissue healing, whereas impaired clearance drives chronic inflammation and maladaptive tissue remodeling. We review the molecular mechanisms governing efferocytosis, including the interplay of find-me, eat-me, and don't-eat-me signals with receptor-mediated cytoskeletal remodeling and lysosomal degradation. We highlight how efferocytosis drives lipid efflux, fatty acid oxidation, amino acid catabolism, and nucleotide recycling, processes that sustain continual efferocytosis and resolution programming. Defects in these pathways, amplified by proteolytic cleavage of apoptotic cell receptors, dysregulated metabolism, and inflammatory mediators, underlie impaired efferocytosis in atherosclerosis, myocardial infarction, vascular aging, and metabolic diseases. Finally, we discuss emerging concepts, including nonprofessional phagocyte contributions, crosstalk with adaptive immunity, and therapeutic strategies to enhance efferocytosis or preserve receptor integrity. Collectively, these insights redefine efferocytosis as more than a cleanup mechanism, positioning it as a central contributor to attenuating cardiometabolic diseases.