Ferroptosis Biomarkers in HPV-Negative Head and Neck Squamous Cell Carcinoma.

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer of the oral cavity, pharynx, larynx and upper airway. HNSCC is subdivided into distinct clinical entities based on the presence or absence of high-risk human papillomavirus (HPV) infection. While HPV-positive HNSCC patients respond better to conventional and targeted therapies than HPV-negative cases, recurrence is more frequent in HPV-negative cases with limited treatment options. Ferroptosis is a form of iron-based programmed cell death caused by excessive lipid peroxide accumulation. Biomarkers of ferroptosis have proven useful for identifying and triggering ferroptosis in models of treatment-resistant cancers. Identifying and understanding ferroptosis biomarker function in HPV-negative HNSCC allows the possibility for more effective treatment strategies. Methods: Literature searches combined with the public online ferroptosis database FerrDB V3 were utilized for the objective identification and classification of established and non-established ferroptosis biomarkers in HPV-negative HNSCC. Additional novel biomarkers were identified based on known roles in HNSCC oncogenesis. Results: A total of 30 ferroptosis biomarkers were identified associated with HPV-negative disease. Biomarkers were grouped according to shared biological functions, with each marker summarized for prognostic and mechanistic roles in HNSCC ferroptosis. Conclusions: The described biomarkers present a means for stratifying tumors for ferroptotic induction, with several offering potential novel methods for overcoming refractory HPV-negative disease. These biomarkers may warrant further investigation into devising future patient-tolerant strategies that selectively activate ferroptosis in HPV-negative HNSCC.