<p>NIMA - related kinase 2 (NEK2), belonging to the NIMA family, is intricately linked to tumorigenesis and tumor progression. Nevertheless, its biological functions and underlying mechanisms in oral squamous cell carcinoma (OSCC) remain elusive. The protein expression level of NEK2 in clinical OSCC samples was evaluated using immunohistochemical staining, and its prognostic impact on OSCC patients was analyzed via Kaplan-Meier survival analysis. Additionally, RT-qPCR and Western blot were performed to examine NEK2 mRNA and protein expression levels in OSCC cell lines (SCC4 and Cal27). Scratch wound healing, Transwell, and immunofluorescence assays were conducted to assess the effects of NEK2 overexpression or knockdown on epithelial-mesenchymal transition (EMT), invasion, and migration in OSCC. Subcutaneous xenograft and tail vein pulmonary metastasis models in nude mice were further employed to elucidate the role of NEK2 in OSCC growth and metastasis in vivo. Moreover, the therapeutic effect of INH1 inhibitor on OSCC tumors was evaluated in nude mice. GO and KEGG enrichment analyses were performed to explore NEK2-regulated pathways in OSCC. The protein manifestation of NEK2 within OSCC tissues was conspicuously elevated in comparison to that in normal oral mucosal tissues. Moreover, elevated NEK2 expression was correlated with suboptimal overall survival (OS) and progression - free survival (PFS). Exhibiting the capacity to induce EMT, NEK2 consequently enhanced the migration and invasion of OSCC cells in vitro. In vivo, it promoted tumor growth, metastasis, and lung colonization. The NEK2 inhibitor, INH1, can effectively suppress the growth, metastasis, and lung colonization of OSCC in animal models. Furthermore, the evidence we have presented suggests that NEK2 may drive the development and progression of OSCC by activating the PI3K - Akt and IL − 17 signaling pathways. NEK2 holds potential as a diagnostic biomarker and a molecular therapeutic target for OSCC patients.</p>