A review on cellular ferroptosis in traumatic brain injury: Mechanisms and therapeutic implications

Traumatic brain injury (TBI) remains a major cause of mortality and long-term neurological disability worldwide, with secondary brain injury playing a critical role in disease progression. Increasing evidence indicates that ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is a key contributor to secondary neuronal damage after TBI. This review systematically summarizes the core mechanisms of ferroptosis in TBI, focusing on blood-brain barrier (BBB) disruption-associated iron dysregulation, polyunsaturated fatty acids (PUFAs)-driven lipid peroxidation, and dysfunction of the glutathione-glutathione peroxidase 4 (GSH-GPX4) axis. We further highlight the extensive crosstalk between ferroptosis and other regulated cell death pathways, including apoptosis, necroptosis, and pyroptosis, mediated by shared upstream triggers and key molecular nodes. Ferroptosis is discussed in a stage-dependent manner across the acute, subacute, and chronic phases of TBI. Emerging ferroptosis-targeted therapeutic strategies, including ferroptosis inhibitors, traditional Chinese medicine (TCM)-derived compounds, gene therapy, and nanomaterial-based delivery systems, are critically reviewed. Finally, current translational challenges and future perspectives for ferroptosis-targeted precision therapy in TBI are discussed.