MTHFD2-Mediated Ubiquitination and Degradation of FOXO1 Promote Tongue Squamous Cell Carcinoma Progression

Abstract Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a pivotal enzyme in one-carbon metabolism, is significantly overexpressed in tongue squamous cell carcinoma (TSCC) and correlates with poor patient prognosis. Functional studies demonstrate that MTHFD2 drives TSCC proliferation and migration in vitro and in vivo, whereas its inhibition suppresses tumor progression. Mechanistically, MTHFD2 orchestrates a dual posttranslational modification cascade: Through its enzymatic activity, it simultaneously induces forkhead box O1 (FOXO1) hypermethylation and ubiquitination, ultimately triggering ubiquitin–proteasome degradation of this tumor suppressor. This methylation-primed degradation axis is clinically validated by the inverse MTHFD2-high/FOXO1-low expression pattern in TSCC specimens, which predicts adverse outcomes. Critically, pharmacologic inhibition of MTHFD2 (e.g., DS18561882) blocks FOXO1 degradation, establishing the MTHFD2–FOXO1 axis as a promising therapeutic target for TSCC through its novel metabolic–epigenetic regulatory mechanism. Implications: This study identifies the MTHFD2–FOXO1 axis as a druggable metabolic–epigenetic pathway in TSCC, providing both a prognostic marker and a therapeutic target.