From scavenger to victim: mechanism and treatment of microglial ferroptosis in white matter injury disease.

Failure of myelin repair is a shared pathological feature of white matter injury (WMI)-associated diseases, including Alzheimer's disease (AD), vascular dementia (VaD), and multiple sclerosis (MS), but the underlying mechanisms remain incompletely understood. Microglia, the resident innate immune cells of the central nervous system (CNS), contribute to white matter homeostasis by clearing myelin debris and supporting remyelination. Within the iron- and lipid-rich white matter microenvironment, sustained uptake of myelin and oligodendroglial debris may impose phagocytic and metabolic stress on microglia, thereby increasing their susceptibility to ferroptosis, an iron-dependent form of regulated cell death driven by membrane phospholipid peroxidation. This susceptibility is regulated by interconnected mechanisms involving ferritinophagy-associated iron dysregulation, ACSL4/NOX2/15-LOX-related lipid peroxidation, and impaired endogenous ferroptosis-defense systems. Microglial responses are also heterogeneous: disease-associated, demyelination-associated, white matter-associated, lipid-droplet-accumulating, and degenerative microglial programs represent partially overlapping and context-dependent states rather than a proven linear trajectory. In susceptible microglial subsets, ferroptosis or ferroptosis-associated dysfunction may impair debris clearance and trophic support while promoting oxidized lipid accumulation and inflammatory signaling, thereby limiting remyelination. This review summarizes current evidence on the molecular mechanisms, multicellular interactions, microglial states, disease contexts, and therapeutic strategies associated with microglial ferroptosis in WMI. We further propose a functional therapeutic-window framework based on phagocytic competence, iron-lipid handling capacity, antioxidant reserve, and evidence of ferroptotic injury, and discuss major challenges in clinical translation. Overall, current evidence supports microglial ferroptosis as a context-dependent contributor to myelin repair failure rather than a universal determinant.