Abstract
BACKGROUND: Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor in adults, with an average survival time of less than 15 months despite treatment. Recurrence and chemotherapy resistance are major challenges, with ferroptosis emerging as a potential mechanism contributing to chemotherapy resistance. The role of oxidative stress-induced growth inhibitor 1 (OSGIN1) in GBM, particularly its localization and function, remains poorly understood, though it is associated with poor prognosis. MATERIAL AND METHODS: We utilized bioinformatics to analyze OSGIN1 expression and GBM patient prognosis from the Cancer Genome Atlas (TCGA). Experimental approaches included C-terminal EGFP tagging of OSGIN1, overexpression, and knockdown experiments in GBM cells. We assessed the effects on cell proliferation, apoptosis, and ferroptosis sensitivity using CCK8 assays, flow cytometry, and lipid peroxidation sensors. The relationship between OSGIN1 and drug sensitivity was explored using data from the Cancer Therapeutics Response Portal (CTRP). Regulatory interactions between OSGIN1 and the cystine transporter SLC7A11 were investigated through polymerase chain reaction, Western blotting, dual luciferase assays, and chromatin immunoprecipitation. RESULTS: High OSGIN1 expression correlates with poor prognosis in GBM. OSGIN1 does not localize with mitochondria in GBM cells nor induce apoptosis. Instead, OSGIN1-modulated cells exhibited altered ferroptosis sensitivity. Knockdown of OSGIN1 increased ferroptosis sensitivity, an effect reversible in OSGIN1-rescued cells. Moreover, OSGIN1 positively regulates SLC7A11 expression, impacting cystine uptake and ferroptosis resistance. Animal models confirmed that GBM cells overexpressing OSGIN1 are more resistant to ferroptosis. CONCLUSION: OSGIN1 is a prognostic marker and potential therapeutic target in GBM. It regulates SLC7A11 expression and contributes to ferroptosis resistance, highlighting its role in the chemotherapeutic response. Targeting OSGIN1 could enhance GBM treatment efficacy by modulating ferroptosis sensitivity.