SHMT2 Suppression Disrupts Redox Homeostasis and Induces Ferroptosis Through the GSH–GPX4 Axis in Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) remains one of the most prevalent and aggressive malignancies worldwide. Serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism, is essential for tumor cell proliferation and redox homeostasis. Whether SHMT2 regulates ferroptosis, an iron-dependent form of regulated cell death, in HNSCC remains unknown. Here, we demonstrate that SHMT2 suppression induces ferroptotic cell death in HNSCC cells, as evidenced by increased lipid peroxidation and elevated prostaglandin-endoperoxide synthase 2 (PTGS2, also known as COX-2) expression. Mechanistically, SHMT2 suppression decreased the intracellular GSH/GSSG ratio, while exogenous GSH partially restored cell viability and attenuated lipid peroxidation. Moreover, SHMT2 suppression reduced GPX4 protein levels, whereas SHMT2 overexpression increased GPX4 abundance. Conversely, GPX4 overexpression had little effect on SHMT2, placing SHMT2 upstream of GPX4. Functionally, GPX4 overexpression partially restored cell viability and reduced lipid peroxidation in SHMT2-knockdown cells, further supporting a functional role for GPX4 downstream of SHMT2. Both genetic and pharmacological inhibition of SHMT2 enhanced erastin-induced ferroptosis in vitro, while SHMT2 knockdown potentiated the antitumor activity of erastin in female BALB/c nude mouse xenografts. Collectively, our study identifies a novel SHMT2-regulated GSH–GPX4 axis that mediates ferroptosis in HNSCC and highlights SHMT2 suppression as a potential therapeutic strategy for head and neck cancer.