CircFOXO3 Upregulation Mediates the Radioresistance of Glioblastoma by Affecting Cellular Metabolome

Abstract Radioresistance remains an important barrier to the treatment of glioblastoma multiforme (GBM), which is the most prevalent and lethal brain cancer in adults. Metabolic alterations contribute to radioresistance through various mechanisms, including activation of antioxidant responses to counteract reactive oxygen species (ROS) and DNA repair. In this study, we observed a significant up-regulation of circFOXO3 in glioma cells upon exposure to radiation and recurrent GBM tissues. Knockdown of circFOXO3 enhanced radiosensitivity in glioma cells. An assay of orthotopic GBM animal model in vivo indicated that inhibition of circFOXO3 significantly suppressed GBM progression and prolonged survival time. Overexpression of circFOXO3 significantly attenuated radiosensitivity in glioma cells. Additionally, metabolomics analysis revealed substantial alterations in the metabolomic profiles between the circFOXO3-OE and control groups following irradiation, particularly involving lipids and lipid-like molecules, organic acids and derivatives, and organoheterocyclic compounds. Moreover, suppression of circFOXO3 increased levels of pro-apoptotic proteins Caspase 7 and Bax while decreasing Bcl-2 levels after radiotherapy. Our findings establish the crucial role played by circFOXO3 in tumor radioresistance through modulation of metabolites, highlighting its potential as a diagnostic and therapeutic target for GBM.