Ferroptosis-associated RNA-binding proteins predict clinical outcomes in head and neck squamous cell carcinoma.

Background: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with limited improvements in survival outcomes. Increasing evidence highlights the role of ferroptosis, an iron-dependent form of regulated cell death, and RNA-binding proteins (RBPs) in tumor progression. However, the prognostic significance of ferroptosis-associated RBPs in HNSCC remains unclear. This study aimed to develop and validate a ferroptosis-associated RBP signature to improve survival prediction and explore its relationship with the immune microenvironment in HNSCC. Methods: A prognostic RBP signature was developed through systematic bioinformatics screening of ferroptosis-associated genes in HNSCC cohorts. Utilizing multi-omics data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we performed functional enrichment and pathway analyses using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) to identify ferroptosis-associated RBPs with prognostic relevance in HNSCC. These candidate RBPs were integrated into a Cox proportional-hazards model, rigorously validated against clinical survival endpoints. Results: Univariate Cox regression analysis identified 15 ferroptosis-associated RBPs significantly correlated with patient prognosis (P<0.01). The RBP-based signature demonstrated moderate predictive capability, with an area under the curve (AUC) of 0.688, outperforming traditional clinicopathological parameters in risk stratification. High-risk patients exhibited significantly reduced overall survival compared to low-risk counterparts (log-rank P<0.001). Conclusions: We established the first ferroptosis-associated RBP signature as an independent prognostic biomarker for HNSCC. Beyond prognostic utility, this signature elucidates novel mechanisms linking RBP-mediated ferroptosis to immune evasion in HNSCC, offering therapeutic targets.