Methylenetetrahydrofolate dehydrogenase 2 promotes cutaneous squamous cell carcinoma progression by reprogramming...

Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a pivotal enzyme in one‑carbon metabolism, is upregulated in several cancers, yet its role and mechanisms in cSCC remain unclear. Here, we show that MTHFD2 is significantly overexpressed in cSCC tissues and cell lines. MTHFD2 enhanced cSCC cell proliferation, migration, and invasion while suppressing apoptosis in vitro, and promoted tumor growth in vivo. Mechanistically, MTHFD2 promotes cSCC progression by sustaining glycolytic metabolism and redox homeostasis, while also exerting a non-metabolic function through interaction with fatty acid synthase (FASN), which in turn modulates the PI3K-AKT signaling pathway. Importantly, pharmacological inhibition of MTHFD2 effectively suppressed cSCC cell proliferation in vitro and tumor growth in vivo, highlighting MTHFD2 as a promising therapeutic target.