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

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

  • bioRxiv. 2026 Feb 2:2026.01.30.702627. doi: 10.64898/2026.01.30.702627.
Angeliki Mela 1,  Abby Brand 1 2,  Aayushi Mahajan 3,  Athanassios Dovas 1,  Nelson Humala 3,  Smriti Kanangat 1,  Allison C Kleinstein 4,  Sandra Leskinen 3,  Trang Tt Nguyen 1,  Qiuqiang Gao 1,  Pavan S Upadhyayula 3,  Jia Guo 5 6,  Brian Gill 3,  Markus D Siegelin 1,  Peter A Sims 2,  Brent R Stockwell 1 7 8 9,  Jeffrey N Bruce 3,  Peter Canoll 1 3
Affiliations

Affiliations

  • 1 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
  • 2 Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
  • 3 Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA.
  • 4 Department of Neuroscience and Behavior, Barnard College, Columbia University, New York, NY, USA.
  • 5 Department of Psychiatry, Columbia University, New York, NY, USA.
  • 6 Department of Biomedical Engineering, Columbia University, New York, NY, USA.
  • 7 Department of Chemistry, Irving Institute for Cancer Dynamics, Data Science Institute, Columbia University, New York, NY, USA.
  • 8 Department of Biological Sciences, Columbia University, New York, NY, USA.
  • 9 Herbert Irving Comprehensive Cancer Center, Columbia University Digestive and Liver Disease Research Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
PMID: 41676617 DOI: 10.64898/2026.01.30.702627
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-mutant inhibitors. Furthermore, dietary cysteine-methionine deprivation alone or in combination with convection-enhanced delivery of RSL3 or ivosidenib in vivo significantly prolongs survival of IDH1-mutant tumor-bearing mice. Our findings suggest that targeting cysteine and methionine metabolism in combination with IDH-mutant inhibition provides promising therapeutic strategies for IDH1-mutant gliomas.

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