Microglial Control of Neuronal Ferroptotic Susceptibility: Evidence, Limits and Therapeutic Implications

Ferroptosis is an iron-dependent form of regulated cell death increasingly implicated in neurological disease and injury. Although neuronal ferroptosis has received substantial attention, the contribution of microglia to neuronal ferroptotic susceptibility remains less clearly defined. This review examines how microglia may regulate neuronal responses to ferroptotic stress through iron handling, inflammatory and redox signalling, and extracellular vesicle-mediated communication. Evidence from intracerebral haemorrhage, subarachnoid haemorrhage, Parkinson’s disease, sepsis-associated encephalopathy, and other neurological contexts is evaluated with particular attention to experimental models, cellular specificity, and ferroptosis-related endpoints. Microglial regulation of neuronal iron homeostasis and inflammatory signalling is supported by several mechanistic studies, while microglia-derived extracellular vesicles provide an additional route through which iron and regulatory molecules may be delivered. However, evidence remains heterogeneous, and ferroptosis occurring within microglia themselves must be distinguished from neuronal ferroptosis. Important uncertainties include whether microglia directly transfer iron to neurons, whether microglia-specific manipulation can alter neuronal ferroptosis in vivo, and how consistently ferroptosis-associated endpoints distinguish ferroptosis from other forms of neuronal injury. Therapeutically, clinical studies of non-selective brain iron chelation caution against indiscriminate reduction in brain iron. Cell- and pathway-selective modulation of microglial iron handling or microglia–neuron signalling therefore represents a potential therapeutic direction that requires further validation.