Abstract
BACKGROUND: Lung squamous cell carcinoma (LUSC) remains an aggressive malignancy with limited therapeutic options and poor prognosis. Recent studies have identified disulfidptosis as a novel form of metabolic stress-induced cell death, but its clinical implications in LUSC remain unexplored. This study investigates the prognostic value of disulfidptosis-related genes (DRGs) in LUSC. METHODS: We analyzed transcriptomic data from TCGA-LUSC cohort and identified DRGs through intersection with established disulfidptosis-related gene sets. A protein-protein interaction (PPI) network was constructed, and univariate Cox regression was performed to select prognostic genes. A risk score model was developed using multivariate Cox regression. The model's performance was evaluated using ROC curve and Kaplan-Meier analyses. Functional enrichment and immune microenvironment analyses were conducted to explore potential mechanisms. RESULTS: We identified 9 prognostic DRGs (FHOD1, ORC5, TRIR, ALKBH1, EPS8L2, MBLAC1, MYADM, HTRA2, and SRI) that significantly correlated with patient survival. The risk score model effectively stratified patients into high- and low-risk groups (P < 0.001), with C-index values of 0.78 at 1 year and 0.75 at 3 years. High-risk patients showed enriched cytokine-cytokine receptor interactions and immunosuppressive microenvironments, while low-risk patients exhibited activated metabolic pathways. Experimental validation confirmed ORC5's oncogenic role in promoting proliferation and invasion. CONCLUSION: We established a novel 9-gene prognostic signature based on disulfidptosis-related genes that effectively predicts LUSC outcomes. These findings highlight the clinical relevance of disulfidptosis in LUSC and provide potential biomarkers for risk stratification and therapeutic targeting.