The immune-metabolism interactome in efferocytosis: a new paradigm for the central nervous system diseases revealed by single-cell sequencing analysis.

Efferocytosis is a process that maintains tissue homeostasis by removing apoptotic cells (ACs) by professional or non-professional phagocytes. The intricate process can be categorized into recognition of ACs, engulfment of ACs, and degradation of efferosomes. Aberrations in efferocytosis result in inadequate clearance of ACs, leading to prolonged inflammation that is implicated in the development and progression of various human diseases. Most central nervous system (CNS) diseases are associated with dysregulation of inflammatory homeostasis. Microglia, the resident immune cells of the CNS, play a primary role in efferocytosis in the brain, which is essential for maintaining the homeostasis of the internal environment. In this review, we summarize the current knowledge of the basic processes of efferocytosis and its indispensable role in the developing and aging brain. Additionally, we discuss the regulatory role of immune-metabolism crosstalk and the insights from single-cell sequencing analysis in dissecting microglial heterogeneity during efferocytosis. We also focus on recent discoveries regarding the critical role of efferocytosis in several CNS diseases, including cerebral ischemia, intracerebral hemorrhage, traumatic brain injury, major depressive disorder, glioblastoma multiforme, Alzheimer's disease, and Parkinson's disease. Finally, we outline potential therapeutic strategies and existing challenges, emphasizing the need for context-specific targeting to improve CNS disease outcomes. © 2026 The Pathological Society of Great Britain and Ireland.