Efferocytosis: unifying pathogenic hub in metabolic disorders-mechanistic landscapes, targeted therapies and...

Metabolic disorders, such as obesity, diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and atherosclerosis, collectively pose a severe global public health crisis. Systemic chronic low-grade inflammation caused by metabolic stress, namely metaflammation, is universally present in metabolic disorders. This pathological trait drives causal interactions and synergistic deterioration among distinct metabolic disorders, and cannot be efficiently alleviated by conventional clinical anti-inflammatory drugs. Efferocytosis refers to the programmed clearance of apoptotic cells mediated by phagocytes such as macrophages. It is indispensable for maintaining innate immune homeostasis, facilitating the resolution of metaflammation, and balancing metabolic microenvironments. This review comprehensively outlines the core characteristics and molecular mechanisms of efferocytosis, illustrates its regulatory networks in multiple metabolic disorders, concludes current therapeutic strategies targeting efferocytosis for metabolic disorders, and discusses the controversies and translational challenges of relevant interventions. This review systemically elucidates the shared core pathological mechanisms of defective efferocytosis underlying the interactive and progressive progression of multiple metabolic disorders, lays a theoretical foundation for the development of early diagnostic biomarkers and novel immune-targeted intervention strategies for metaflammation, and provides evidence-based rationale for translational research and clinical practice of related metabolic disorders.