Hypoxia-related gene signatures and PRMT5 define radiation resistance and prognosis in head and neck squamous cell carcinoma

Tumor hypoxia is known to play a crucial role in the progression and treatment resistance of head and neck squamous cell carcinoma (HNSCC). This study aimed to evaluate the prognostic significance of hypoxia-related gene signatures and to explore the molecular mechanisms underlying radiation resistance. Patients with HNSCC were divided into hypoxia-related low-risk (hypoxia-LR; n = 198) and high-risk (hypoxia-HR; n = 316) subgroups based on hypoxia-associated gene expression profiles. Survival outcomes were analyzed using Kaplan–Meier and Cox regression analyses, and the hypoxia-related signature was validated across three independent cohorts. Additionally, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) pathway analysis was performed to identify molecular pathways associated with radiation resistance, with a particular focus on post-translational modifications. The hypoxia-HR subgroup showed significantly poorer 5-year overall survival (OS) and recurrence-free survival rates than the hypoxia-LR subgroup ( p = 0.04 and 0.02, respectively). The hypoxia-related signature remained an independent prognostic factor regardless of HPV status and showed a strong correlation with radiotherapy response. Pathway analysis revealed enrichment of post-translational modification processes, highlighting protein arginine methyltransferase 5 (PRMT5) as a key regulator. Functional experiments demonstrated that PRMT5 inhibition abolished radiation resistance in resistant HNSCC cell lines, whereas PRMT5 overexpression conferred resistance in standard cell lines. Both hypoxia-related molecular signatures and PRMT5 expression play critical roles in determining radiation response and prognosis in HNSCC. Targeting PRMT5 in conjunction with hypoxia-related biomarkers may enable personalized therapeutic strategies to enhance radiotherapy efficacy in head and neck cancer.