Ferroptosis-Mediated Radiosensitization in Glioblastoma: Preclinical Insights and Translational Opportunities

Glioblastoma (GBM) remains the most common and most aggressive primary malignant brain tumor in adults, and despite maximal safe resection with adjuvant radiotherapy (RT) and temozolomide (TMZ), median overall survival remains 12–15 months with near-universal recurrence. Ferroptosis, an iron-dependent form of regulated cell death driven by the accumulation of lipid peroxides, has emerged as a distinctive vulnerability in GBM, whose iron-avid phenotype, polyunsaturated fatty acid-rich milieu, and high oxygen consumption create a permissive substrate for lipid peroxidation. In this review, we synthesize preclinical evidence positioning ferroptosis as a determinant of GBM radiosensitivity and evaluate strategies to exploit it. We first outline core ferroptosis biology and GBM-specific modifiers of ferroptotic susceptibility, including TFR1-mediated iron import, grade-dependent glutathione peroxidase 4 (GPX4) expression, acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) levels, transsulfuration, NRF2, p53, non-coding RNAs, and the relative resistance of mesenchymal tumors and glioma stem cells. We then examine mechanisms of radiation-induced ferroptosis, in which RT upregulates ACSL4 and depletes glutathione (GSH) while simultaneously provoking adaptive responses that induce the cystine transporter solute carrier family 7 member 11 (SLC7A11) and GPX4, alongside hypoxia-, IFI16/HMOX1-, and lncRNA-mediated programs that sustain radioresistance, noting that recurrent tumors display a ferroptosis-primed profile after chemoradiation. Radiosensitization strategies are reviewed across pharmacologic ferroptosis inducers (classes I-IV), repurposed agents, NRF2 inhibition, genetic targeting of ferroptosis mediators, and blood–brain barrier-penetrant nanoplatforms that couple iron delivery, high-Z radiation deposition, and antioxidant disruption. We further address the immunologic consequences of ferroptosis within the immunosuppressive GBM microenvironment, the countervailing problem of radiation-induced brain injury and candidate neuroprotective approaches, the potential convergence of FLASH RT with iron-dependent differential sparing, and comparative evidence of ferroptosis-RT synergy in other treatment-resistant malignancies. Finally, we appraise candidate biomarkers and ferroptosis-related gene signatures, and close by addressing open questions and current translational hurdles facing the field.