Ferroptosis in the nervous system: metabolic regulation, iron homeostasis, and translational therapeutic strategies

Neurological diseases remain a leading cause of disability and mortality worldwide, yet effective disease-modifying therapies are still lacking. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as an important contributor to neuronal injury. In this review, we introduce the “Iron-Brain Nexus” as an integrative framework linking regional iron metabolism with the unique metabolic characteristics of the nervous system, including high polyunsaturated fatty acid content, elevated oxidative metabolism, and limited antioxidant capacity, to explain selective neuronal vulnerability to ferroptosis. We summarize the physiological interplay between brain metabolism and iron homeostasis and discuss how disruption of this balance promotes ferroptotic susceptibility. We further critically evaluate current evidence linking ferroptosis to Alzheimer’s disease, Parkinson’s disease, and stroke, distinguishing well-supported mechanisms from emerging findings across different levels of evidence. Finally, we review ferroptosis-targeted therapeutic strategies, including iron chelation, lipid peroxidation inhibitors, antioxidants, and gene-targeted approaches, with emphasis on their translational opportunities and challenges, particularly blood-brain barrier penetration, target specificity, and neuronal safety. Collectively, this review highlights the “Iron-Brain Nexus” as a framework for understanding brain-specific ferroptosis and guiding biomarker-informed therapeutic development for neurological diseases.