Investigating the oncogenic potential of MTHFD2 in oral squamous cell carcinoma

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial bifunctional enzyme, is reportedly upregulated in several malignancies, demonstrating cancer-associated dysregulation. However, its functional contribution to oral squamous cell carcinoma (OSCC) progression remains unexplored. Therefore, this study aimed to investigate the role of MTHFD2 in OSCC development. MTHFD2 expression was assessed in OSCC biospecimens using integrated bioinformatics, immunohistochemistry, and immunoblotting techniques. Survival analysis was conducted utilizing the Kaplan–Meier methodology. The MTHFD2-associated mechanisms involved in OSCC were explored via enrichment analysis. Genetic suppression of MTHFD2 was employed to evaluate the functional consequences on OSCC cell proliferation (Cell Counting Kit-8 assay), apoptosis (flow cytometry), migration (wound healing assay), and invasion (Matrigel transmigration). MTHFD2 expression was considerably elevated in OSCC lesions and cellular models. MTHFD2 overexpression in OSCC tissues correlated with advanced Tumor, Node, and Metastasis stage (P = 0.002), regional lymph node metastasis (P = 0.043), and elevated Ki67 expression (P < 0.001). Furthermore, increased MTHFD2 levels were associated with poor overall survival outcomes in patients with OSCC (P < 0.05). Pathway enrichment analysis revealed that MTHFD2 upregulation was closely linked to the dysregulation of key neoplastic processes. Stable MTHFD2 depletion attenuated cell proliferation in vitro and diminished xenograft tumorigenicity in vivo (P < 0.05). Additionally, MTHFD2 ablation induced OSCC cell apoptosis and reduced cell migration and invasion. This study indicates that MTHFD2 is critical for OSCC progression and may serve as a potential therapeutic target, though further validation is needed to confirm its independent prognostic value and clinical applicability.