2. Academic Validation
  3. Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism

Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism

  • Proc Natl Acad Sci U S A. 2020 May 5;117(18):9964-9972. doi: 10.1073/pnas.1913633117.
Di Yu 1 2 3,  Yang Liu 1,  Yiqiang Zhou 1,  Victor Ruiz-Rodado 1,  Mioara Larion 1,  Guowang Xu 4,  Chunzhang Yang 5
Affiliations

Affiliations

  • 1 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, MD 20892.
  • 2 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023 Dalian, China.
  • 3 University of Chinese Academy of Sciences, 100049 Beijing, China.
  • 4 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023 Dalian, China; xugw@dicp.ac.cn yangc2@nih.gov.
  • 5 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, MD 20892; xugw@dicp.ac.cn yangc2@nih.gov.
PMID: 32312817 DOI: 10.1073/pnas.1913633117
Abstract

Isocitrate dehydrogenase (IDH) mutation is a common genetic abnormality in human malignancies characterized by remarkable metabolic reprogramming. Our present study demonstrated that IDH1-mutated cells showed elevated levels of Reactive Oxygen Species and higher demands on Nrf2-guided glutathione de novo synthesis. Our findings showed that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, served as a potent Nrf2 inhibitor, which exhibited selective cytotoxicity to patient-derived IDH1-mutated glioma cells in vitro and in vivo. Mechanistically, triptolide compromised the expression of GCLC, GCLM, and SLC7A11, which disrupted glutathione metabolism and established synthetic lethality with Reactive Oxygen Species derived from IDH1 mutant neomorphic activity. Our findings highlight triptolide as a valuable therapeutic approach for IDH1-mutated malignancies by targeting the Nrf2-driven glutathione synthesis pathway.

Keywords

IDH1 mutation; Nrf2; glutathione; reactive oxygen species; triptolide.

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