Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers

Mariluz Soula, Ross A. Weber, Omkar Zilka, Hanan Alwaseem, Konnor La, Frederick Yen, Henrik Molina, Javier Garcia-Bermudez, Derek A. Pratt, Kıvanç Birsoy

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Cancer cells rewire their metabolism and rely on endogenous antioxidants to mitigate lethal oxidative damage to lipids. However, the metabolic processes that modulate the response to lipid peroxidation are poorly defined. Using genetic screens, we compared metabolic genes essential for proliferation upon inhibition of cystine uptake or glutathione peroxidase-4 (GPX4). Interestingly, very few genes were commonly required under both conditions, suggesting that cystine limitation and GPX4 inhibition may impair proliferation via distinct mechanisms. Our screens also identify tetrahydrobiopterin (BH4) biosynthesis as an essential metabolic pathway upon GPX4 inhibition. Mechanistically, BH4 is a potent radical-trapping antioxidant that protects lipid membranes from autoxidation, alone and in synergy with vitamin E. Dihydrofolate reductase catalyzes the regeneration of BH4, and its inhibition by methotrexate synergizes with GPX4 inhibition. Altogether, our work identifies the mechanism by which BH4 acts as an endogenous antioxidant and provides a compendium of metabolic modifiers of lipid peroxidation. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)1351-1360
Number of pages10
JournalNature chemical biology
Volume16
Issue number12
DOIs
StatePublished - Dec 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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