Systemic Cyst(e)inase Administration Induces Ferroptosis and Synergizes with Temozolomide in Glioblastoma

Abstract

Glioblastoma (GBM), an aggressive primary brain cancer, exhibits therapeutic resistance because of tumor heterogeneity and highly plastic glioma stem cells (GSCs). This study targets the metabolic vulnerability of GSCs to cysteine depletion using Cyst(e)inase, a cysteine-degrading enzyme. In patient-derived GSCs and orthotopic xenograft murine models, Cyst(e)inase inhibited GSC growth and extended animal survival by inducing ferroptosis. Mechanistically, Cyst(e)inase triggered elevated reactive oxygen species, glutathione depletion, and lipid peroxidation, indicative of ferroptosis. Critically, Cyst(e)inase synergized with temozolomide (TMZ), the standard GBM chemotherapy, markedly enhancing its efficacy even in TMZ-resistant xenografts. These findings establish cysteine metabolism as a promising therapeutic target in GBM and position Cyst(e)inase, particularly in combination with TMZ, as a promising therapeutic strategy.