IDH-mutant inhibitors enhance the sensitivity of IDH1-mutant gliomas to cysteine-methionine deprivation and ferroptosis.

ABSTRACT: Cysteine is essential for synthesizing glutathione, the brain's main antioxidant, and cysteine deprivation can trigger ferroptosis. Here, using a new mouse model of IDH1-mutant glioma that recapitulates the characteristics of human IDH1-mutant low-grade gliomas, we demonstrate that IDH1-mutant glioma cells are significantly more vulnerable to cysteine deprivation alone or in combination with the ferroptosis inducer RSL3, compared to IDH1-wildtype glioma cells. In addition, treatments with the IDH-mutant inhibitors vorasidenib and ivosidenib further sensitize the cells to ferroptosis. Metabolomics analysis reveals that IDH1-mutant cells have altered cysteine and methionine metabolism with deficiency in transsulfuration, which is further exacerbated by cysteine-methionine deprivation and IDH

SUBMITTER: Mela A 

PROVIDER: S-EPMC12889447 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature