Abstract / Summary
Abstract Background: Radioresistance limits the efficacy of radiotherapy in nasopharyngeal carcinoma (NPC). We explored ferroptosis-related genes as candidate biomarkers and radiosensitivity regulators to counter this challenge. Methods and Results: We screened ferroptosis-related differentially expressed genes (DEGs) using transcriptomic data from Gene Expression Omnibus (GEO, GSE48503), The Cancer Genome Atlas (TCGA), and ferroptosis gene sets from FerrDb and GeneCards. Functional enrichment and protein-protein interaction (PPI) network analyses were performed. A prognostic model was constructed and internally validated via Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. We knocked down and overexpressed candidate genes in C666-1 cells, then assessed clonogenic survival, apoptosis, and oxidative stress via malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), and protein blotting. We identified 28 FRDEGs enriched in hypoxia and oxidative stress pathways. A robust prognostic signature based on SLC2A3 and TRIB3 was established, demonstrating significant predictive power for patient survival (AUCs: 0.700-0.836). Silencing SLC2A3 or TRIB3 significantly enhanced radiosensitivity by reducing clonogenic survival, while overexpression promoted radioresistance. Radiation-induced apoptosis and oxidative stress were markedly increased following knockdown of either individual gene, as indicated by elevated ROS/MDA and decreased SOD. Molecular analyses validated the computational prediction that SLC2A3 and TRIB3 regulate radiation response through apoptosis and oxidative stress. Conclusions: The SLC2A3 / TRIB3 gene signature serves as a novel prognostic biomarker and predictor of radiosensitivity in NPC. Our integrated analysis confirms their functional roles in regulating apoptosis and oxidative stress, suggesting their potential as therapeutic targets for overcoming radioresistance.