Selenium Inhibits HNSCC By Activating Ferroptosis

Trace elements play crucial roles in tumorigenesis, yet their molecular mechanisms in cancer suppression remain incompletely understood. This study elucidates the therapeutic potential of selenium (Se) in head and neck squamous cell carcinoma (HNSCC) through systematic investigation of two selenoproteins - Se-binding Protein 1 (SBP1) and Glutathione Peroxidase 4 (GPX4) - focusing on their ferroptosis-regulating functions within the selenoprotein network. Multi-platform analysis integrating bioinformatics (TCGA/GEO databases), western blotting, and immunohistochemical staining was conducted to map SBP1/GPX4 expression patterns across HNSCC specimens and cell lines. Protein-protein interactions were characterized through immunofluorescence colocalization and co-immunoprecipitation (co-IP) assays. Functional validation employed CRISPR-Cas9-mediated gene editing, patient-derived organoids, and orthotopic xenograft models, complemented by comprehensive assessments using CCK-8 proliferation, EdU incorporation, and Transwell migration assays. Our findings revealed that SBP1 is underexpressed in HNSCC and correlates with poor clinical prognosis, whereas GPX4 exhibits an opposite expression pattern. Mechanistic investigations revealed a direct interaction between SBP1 and GPX4 was observed, with selenocysteine serving as the interaction site. Functional studies confirmed that Se-mediated SBP1 induction effectively suppressed malignant phenotypes in both cellular and preclinical models, whereas genetic depletion of SBP1 fundamentally reversed Se's tumor-suppressive effects through ferroptosis pathway dysregulation. Our findings establish SBP1 as a novel Se-responsive ferroptosis inducer that antagonizes GPX4-mediated cytoprotection in HNSCC. This Se-selenoprotein axis provides a mechanistic basis for developing precision treatment strategies targeting ferroptosis vulnerabilities in HNSCC.