CCND1 Stability Regulated by USP7 Deubiquitination Controls Glioma Radioresistance via Ferroptosis.

Dysregulation of Cyclin D1 (CCND1) is implicated in various cancers, but its specific contribution to glioma radioresistance and the associated regulatory mechanisms remain largely unexplored. This research aimed to elucidate the functional role and underlying mechanisms of CCND1 in glioma radioresistance. Our findings revealed that CCND1 is significantly upregulated in glioma tissues, which correlates with a poor prognosis. Furthermore, CCND1 knockdown inhibited proliferation, triggered apoptosis, and augmented radiosensitivity in glioma cells. Additionally, CCND1 depletion sensitized glioma cells to irradiation by driving ferroptosis, as indicated by elevated reactive oxygen species (ROS) production, lipid peroxidation, and intracellular Fe2+ accumulation. Mechanistically, USP7 was identified to stabilize the CCND1 protein via K48-linked deubiquitination. Notably, the ectopic expression of USP7 reversed the impacts of CCND1 knockdown on radiosensitivity, ferroptosis, cellular proliferation, and apoptosis. Altogether, our data indicate that the stabilization of CCND1 mediated by USP7 promotes radioresistance in glioma by suppressing ferroptosis. Therefore, targeting USP7 may serve as a promising therapeutic approach to augment the efficacy of radiotherapy in glioma.