A Selective Pro-Oxidant Drives Redox Reprogramming to Induce Ferroptosis and Immune Remodeling in Glioblastoma

Glioblastoma remains a highly lethal malignancy characterized by profound therapeutic resistance driven, in part, by adaptive redox homeostasis. Although elevated reactive oxygen species support tumor progression, glioblastoma relies on robust antioxidant systems including the SLC7A11-GPX4 axis to buffer oxidative stress, creating a targetable vulnerability. Here, we investigate Rosasina, a sodium-chlorite (NaClO₂)-derived, redox-active small molecule, as a selective pro-oxidant strategy to disrupt glioblastoma antioxidant resilience and induce ferroptotic cell death. Rosasina preferentially increased intracellular ROS in glioblastoma cells relative to normal human astrocytes, with hydrogen peroxide representing the predominant ROS species. This oxidative shift was accompanied by expansion of the labile iron pool and enhanced lipid peroxidation. In orthotopic glioblastoma models, Rosasina was well tolerated, significantly reduced tumor growth, prolonged survival, and exhibited no evidence of treatment-related systemic toxicity, with preserved histological integrity of major organs. Mechanistically, Rosasina induces a coordinated pro-ferroptotic transcriptional program, characterized by upregulation of iron uptake and lipid peroxidation pathways (NCOA4, NOX5, ACSL4, TFRC), alongside suppression of antioxidant defenses, including GPX4, GCH1, SCD1, and SLC7A11. In addition to its tumor-intrinsic effects, Rosasina promoted macrophage polarization toward an anti-tumor, pro-inflammatory M1-like phenotype without compromising macrophage viability, suggesting a potential role in tumor immune microenvironment reprogramming. Collectively, these findings establish Rosasina as a redox-directed therapeutic that selectively exploits the oxidative vulnerabilities of glioblastoma to induce ferroptosis simultaneously promoting antitumor immune reprogramming. This study provides a mechanistic framework for the development of redox-targeted therapies for glioblastoma.