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  • 标题:Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism
  • 本地全文:下载
  • 作者:Di Yu ; Yang Liu ; Yiqiang Zhou
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2020
  • 卷号:117
  • 期号:18
  • 页码:9964-9972
  • DOI:10.1073/pnas.1913633117
  • 出版社:The National Academy of Sciences of the United States of America
  • 摘要: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.
  • 关键词:triptolide ; IDH1 mutation ; Nrf2 ; glutathione ; reactive oxygen species
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