Tirzepatide Induces Ferroptosis in Glioblastoma Cell Lines via the SOX2/SLC7A11 Axis: A Potential Therapeutic Strategy for Glioma Treatment

ABSTRACT Tirzepatide, a dual agonist for glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptors used in type 2 diabetes and obesity management, was investigated for its effects on glioma cells, focusing on its potential to induce ferroptosis. Tirzepatide treatment significantly inhibited glioma cell proliferation and migration, as demonstrated by the CCK‐8 and Transwell migration assays. Tirzepatide also induced lipid peroxidation, evidenced by increased ROS levels, elevated MDA production, and reduced SOD activity, while the GSH/GSSG ratio was decreased, reflecting oxidative stress. Ferroptosis was further confirmed by increased Fe 2+ concentrations and alterations in iron metabolism‐related genes (Ferritin and TFR1) and lipid metabolism‐related genes (ACSL4 and GPX4). Tirzepatide also inhibited the SOX2/SLC7A11 axis, which plays a critical role in resisting ferroptosis. Fer‐1, a ferroptosis inhibitor, or SOX2 overexpression, markedly reduced Tirzepatide's effects on proliferation, migration, lipid peroxidation, and ferroptosis, highlighting the critical role of the SOX2/SLC7A11 axis in mediating these effects. These findings indicate that Tirzepatide inhibits glioma cell growth by inducing ferroptosis, presenting a potential therapeutic approach for glioma.