Abstract / Summary
Abstract Objective: Head and neck squamous cell carcinoma (HNSC) is highly heterogeneous and has poor prognosis. Mitochondrial dysfunction contributes to metabolic reprogramming and immune regulation, but its prognostic value in HNSC remains unclear. This study aimed to identify mitochondrial dysfunction-related prognostic genes, construct a risk model, and explore associations with the immune microenvironment, mutations, and immunotherapy response. Methods: TCGA-HNSC transcriptomic data were integrated with mitochondrial dysfunction-related genes from GeneCards. Prognostic genes were screened by differential expression, log-rank testing, and Cox regression. Patients were divided 7:3 into training and testing cohorts. A model was constructed using univariate Cox, LASSO, stepwise, and multivariate Cox regression and validated in the training, testing, TCGA-HNSC, and GSE41613 cohorts. CIBERSORT, ssGSEA, ESTIMATE, TIDE, and an independent immunotherapy cohort were used for immune analyses. Somatic mutations and tumor mutational burden were evaluated. PPP1R3A was validated in CAL27 and SCC-25 cells by overexpression, knockdown, qRT-PCR, and Western blotting. Results: Ninety-eight mitochondrial dysfunction-related prognostic genes were identified, yielding a 10-gene model. The model stratified patients into high- and low-risk groups across internal and external cohorts, with significantly poorer survival in the high-risk group. Risk score was an independent prognostic factor. Low-risk patients showed stronger antitumor immune activity and a higher likelihood of immunotherapy benefit. Risk score was associated with tumor mutational burden and mutation patterns. qRT-PCR and Western blotting confirmed PPP1R3A overexpression and knockdown. Conclusion: The 10-gene mitochondrial dysfunction-related signature may support prognostic assessment and risk stratification in HNSC and characterize immune and genomic features relevant to immunotherapy response.