Abstract
BACKGROUND: Radioresistance is fundamental to glioma progression and poor prognosis. Understanding its underlying mechanisms and identifying novel therapeutic targets through elucidating key molecules in glioma radiosensitivity pathways are therefore of significant clinical importance. METHODS: Radiosensitivity-related genes were identified based on radiotherapy response, glioma stemness, and prognosis. A predictive signature was constructed using Lasso-Cox regression and validated via clinicopathological, functional enrichment, immune infiltration, and correlation analyses. GPX8 expression and prognostic significance were assessed by tissue microarray. In vitro functional and radiobiological assays, complemented by in vivo subcutaneous xenograft models using BALB/c nude mice (treated with or without radiotherapy), evaluated the role of GPX8 in regulating malignant progression and radiosensitivity in glioma. RESULTS: The radiosensitivity-related signature demonstrated significant potential in predicting glioma malignancy and prognosis, serving as an indicator of the mesenchymal subtype and contributing to the maintenance of an immunosuppressive microenvironment. GPX8 was overexpressed in high-grade gliomas and correlated with recurrence and poor survival. Knockdown of GPX8 suppressed the malignant biological behaviors of glioma cells. Radiation upregulated GPX8 expression while GPX8 knockdown significantly enhanced the cytotoxicity of radiation and induced apoptosis by promoting oxidative stress and DNA damage. Suppression of GPX8 effectively potentiated radiosensitivity in murine xenograft models and reduced intratumoral infiltration of tumor-associated macrophages. CONCLUSIONS: The radiosensitivity-related signature serves as a significant predictor for assessing glioma malignancy and prognosis. GPX8 acts as a key regulator of malignant phenotypes and radiosensitivity in glioma, positioning it as a promising therapeutic target to counteract both malignant progression and radioresistance.