Differences in ferroptosis sensitivity among neural cells after traumatic brain injury

As an iron-dependent, lipid peroxidation-induced mode of regulated cell death, the difference in sensitivity to ferroptosis among neurons, astrocytes, microglia, and oligodendrocytes is a key breakthrough in deciphering the pathological heterogeneity of traumatic brain injury. Therefore, this review systematically discusses the regulatory mechanisms underlying the differential sensitivity of these cell types to ferroptosis: neurons are highly sensitive due to an imbalance in iron metabolism, enrichment of polyunsaturated fatty acids, and a weak antioxidant system; astrocytes are strongly resistant due to their robust antioxidant capacity and efficient iron buffering ability; the sensitivity of microglia varies with pro-inflammatory/anti-inflammatory phenotypic switching; and oligodendrocytes are moderately sensitive because of the content of rich polyunsaturated fatty acids in their myelin sheaths. Moreover, the review identifies the regulatory mechanisms of the intercellular interaction network: metabolic support from astrocytes, immune regulation from microglia, and nutritional supply from oligodendrocyte myelin sheaths collectively constitute a synergistic regulatory network for the ferroptotic cascade. This review systematically integrates the regulatory mechanisms of multiple pathways, including iron metabolism and lipid metabolism, identifies core regulatory targets for different cell types, and proposes a multi-dimensional intervention strategy that includes regulation of iron metabolism, antioxidants, and nanodelivery systems. This review confirms that intervention in key ferroptosis molecules (e.g., GPX4, SLC7A11, and Nrf2) can greatly alleviate neurological damage after traumatic brain injury and improve neurological function. By closely linking cell type heterogeneity with the molecular mechanisms of ferroptosis, this review proposes a new theoretical framework to decipher the pathological complexity of traumatic brain injury and develop stratified treatment strategies. It provides an important basis for the precise treatment of traumatic brain injury: cell-specific biomarkers and targeted delivery technologies lay a foundation for the clinical translation of ferroptosis-targeted therapy for traumatic brain injury. In the future, it will be necessary to decipher subtype differences using multi-omics approaches and optimize the pharmacokinetics of drugs to realize the clinical application of ferroptosis-targeted therapy for traumatic brain injury.