{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Mao C"],"funding":["NCI NIH HHS"],"pagination":["586-590"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8895686"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["593(7860)"],"pubmed_abstract":["Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism<sup>1-4</sup>. Glutathione peroxidase 4 (GPX4)<sup>5,6</sup> and ferroptosis suppressor protein 1 (FSP1)<sup>7,8</sup> constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate-the substrate and product of dihydroorotate dehydrogenase (DHODH)-attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4<sup>lo"],"journal":["Nature"],"pubmed_title":["DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer."],"pmcid":["PMC8895686"],"funding_grant_id":["P50 CA070907","P30 CA016672","U54 CA224065","R01 CA247992","R01 CA244144","R01 CA181196","R01 CA190370"],"pubmed_authors":["Gan B","Lei G","Lee H","Fang B","Yan Y","Olszewski K","Liu X","Poyurovsky MV","Mao C","Zhang Y","Wu S","Koppula P","Zhuang L"],"additional_accession":[]},"is_claimable":false,"name":"DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.","description":"Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism<sup>1-4</sup>. Glutathione peroxidase 4 (GPX4)<sup>5,6</sup> and ferroptosis suppressor protein 1 (FSP1)<sup>7,8</sup> constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate-the substrate and product of dihydroorotate dehydrogenase (DHODH)-attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4<sup>lo","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 May","modification":"2026-06-03T10:22:35.557Z","creation":"2025-02-18T23:36:42.878Z"},"accession":"S-EPMC8895686","cross_references":{"pubmed":["33981038"],"doi":["10.1038/s41586-021-03539-7"]}}