Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers

By Mariluz Soula, Ross A. Weber, Omkar Zilka, Hanan Alwaseem, Konnor C. La, Frederick S. Yen, H. Molina, J. Garcia-Bermudez, D. Pratt, Kıvanç Birsoy. Nature Chemical Biology, 2020

626 citations recorded by the source corpus.

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. Genetic screens reveal a compendium of metabolic modifiers of lipid peroxidation. Tetrahydrobiopterin is essential under GPX4 inhibition, acting as a radical-trapping antioxidant that inhibits lipid peroxidation and is regenerated by DHFR.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/1b91a0b66497d0bd8895b6690ba89be15cd99b2e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Qing-zhang Tuo
2. P. Lei
3. Brent R. Stockwell

In Molecular Biology

1. Qing-zhang Tuo
2. P. Lei
3. Brent R. Stockwell
4. Scott J. Dixon
5. R. Kang
6. D. Tang
7. M. Conrad
8. James A. Olzmann

In Pulmonary and Respiratory Medicine

1. Qing-zhang Tuo
2. P. Lei
3. Furong Zeng
4. Yu Meng
5. Yihuang Liu
6. Guangtong Deng
7. Xiang Chen
8. Yuming Sun

Citations in the corpus

• The cell biology of ferroptosis (2024, neutral): “S cluster biosynthesis 45 .”
• Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “50,51 Moreover, Zou et al. identi fi ed the oxidative organelles peroxisomes as a crucial factor in driving susceptibility to and evasion from ferroptosis through the synthesis of polyunsaturated ether PLs (PUFA-ePLs), which serve as substrates for lipid peroxidation.”
• Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “, 2020), as well as an enhancer of ferroptosis in a CRISPR loss-of-function screen (Soula et al., 2020).”
• Ferroptosis: mechanisms and links with diseases (2021, background): “BH4 is a potent radicaltrapping antioxidant that protects cells from ferroptosis upon GPX4 inhibition by reducing lipid peroxidation and is regenerated by dihydrofolate reductase (DHFR).(142) Besides, nuclear factor erythroid 2-related factor 2 (Nrf2) may play a role in modulating the cellular ferro”