Integrative multi-omics and preclinical analyses identify miR-4776-5p as a prognostic radiosensitizer for patients undergoing radiotherapy for head-and-neck cancer

Radiotherapy remains a cornerstone treatment for head-and-neck cancer (HNC), yet resistance to radiation therapy significantly limits clinical outcomes. MicroRNAs (miRNAs) have emerged as promising regulators of radiosensitivity; however, the mechanisms by which miRNAs modulate radiosensitivity in HNC remain incompletely understood. In this study, we employed a multi-omics strategy integrating transcriptomic, clinical, and outcome data to investigate miRNA-associated radiosensitivity. Critically, we defined two distinct patient cohorts in the public dataset: one group received only radiotherapy, and the other did not receive radiotherapy. This stratification allowed us to conduct a unique comparative bioinformatics analysis, leading to the identification of miR-4776-5p as a candidate radiosensitizer. Elevated miR-4776-5p expression correlated with improved prognosis, specifically in patients receiving radiotherapy. Functional assays confirmed that miR-4776-5p sensitized FaDu HNC cells to radiation-induced DNA damage and impaired clonogenic survival. Mechanistic analyses demonstrated that miR-4776-5p modulates the cell cycle and DNA damage response pathways, enhancing tumor radiosensitivity. Furthermore, xenograft mouse models validated the radiosensitizing effects of miR-4776-5p in vivo, evidenced by significantly delayed tumor growth following irradiation. These findings highlight miR-4776-5p as a potential biomarker and therapeutic agent to improve radiotherapy efficacy in HNC, supporting further clinical exploration.