Microglial ferroptosis mediated neuroinflammation in central nervous system diseases.

Microglial ferroptosis has become an important pathological mechanism in studies of central nervous system (CNS) diseases. Rather than being viewed only as an endpoint of cell death, ferroptosis in microglia is increasingly recognized as a process that links iron dyshomeostasis, lipid peroxidation, oxidative stress, and immune-inflammatory activation, thereby contributing to the sustained amplification of neuroinflammation. In this review, we summarize the molecular mechanisms by which microglial ferroptosis mediates neuroinflammatory responses, with a focus on iron homeostasis disruption, lipid peroxidation and ROS amplification, collapse of the GPX4-dependent antioxidant defense, mitochondrial ROS generation, and inflammasome activation. We further classify related CNS diseases into three categories according to disease course and pathological features: chronic neurodegenerative and demyelinating diseases, acute CNS injuries, and neuropsychiatric or systemic inflammation-related brain dysfunction. Within this framework, we compare the pathological significance of microglial ferroptosis across different disease contexts. We also discuss potential therapeutic strategies targeting iron homeostasis, lipid peroxidation, antioxidant defenses, inflammatory amplification networks, and microglia-specific delivery systems. Finally, we address current challenges in the field, including insufficient cell-type specificity, inconsistent detection criteria, disease-stage heterogeneity, and barriers to clinical translation. This review provides an integrated perspective on the mechanisms by which microglial ferroptosis drives neuroinflammation and highlights its potential relevance for precision intervention in CNS diseases.