Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy globally, characterized by high invasiveness and poor prognosis. Over half of patients experience recurrence or metastasis within three years, underscoring the limitations of current therapies, especially in inoperable cases, and emphasizing the need to elucidate molecular mechanisms driving its aggressiveness. This study investigates the tumor-suppressive role of HAO2 in the context of dysregulated lipid metabolism and HNSCC pathogenesis. Using an integrated approach, we combined bioinformatic analyses, cellular models, and in vivo experiments to comprehensively evaluate HAO2 expression and functional significance in HNSCC. This included assays to assess proliferation, invasion, migration, and mechanistic interactions involving ubiquitination pathways. HAO2 is significantly downregulated in HNSCC, and its overexpression suppresses tumor growth and modulates lipid metabolism. Expression inversely correlates with key lipid metabolic pathways, suggesting its therapeutic potential in metabolic reprogramming. Clinically, low HAO2 expression correlates with poorer patient survival, supporting its utility as a prognostic biomarker. Functional assays confirm that HAO2 inhibits proliferation, invasion, and migration. Mechanistically, HAO2 promotes ubiquitin-mediated degradation of MYH9 by enhancing its association with the E3 ubiquitin ligase STUB1 and impairing interaction with the deubiquitinating enzyme USP14, collectively enhancing MYH9 ubiquitination and degradation. Our findings unveil the HAO2/STUB1/USP14/MYH9 axis as a pivotal regulatory pathway in HNSCC, providing a mechanistic foundation for clinical translation. These results underscore the potential of HAO2 as a prognostic marker and warrant further clinical validation and investigation into its role in other cancers.