DHODH-mediated ferroptosis defense is a targetable vulnerability in cancer

By Chao Mao, Xiaoguang Liu, Yilei Zhang, Guang Lei, Yuelong Yan, Hyemin Lee, Pranavi Koppula, Shiqi Wu, Zhuang Li, B. Fang and 3 more. Nature, 2021

1,617 citations recorded by the source corpus.

Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1–4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 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 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment. DHO dehydrogenase regulates ferroptosis by preventing mitochondrial lipid peroxidation and its inhibition suppresses growth in tumours with low levels of GPX4.

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

View Paper: https://www.semanticscholar.org/paper/4c5eba57ff6761977caa553eb345962b95427d0d

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Citations in the corpus

The cell biology of ferroptosis (2024, positive): “Moreover, ETC function is necessary for the activity of two mitochondrially localized enzymes that may be able to generate reduced CoQ: dihydroorotate dehydrogenase (DHODH) 37 and glycerol-3-phosphate dehydrogenase 2 (GPD2) 95 .”
Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “134 Furthermore, GCH1 has been identi ﬁ ed as a suppressor of ferroptosis through a two-pronged mechanism.”
Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “Second, DHODH was identified as a mitochondrial suppressor of ferroptosis that functions by reducing mitochondrial CoQ10, analogous to the function of FSP1 in extramitochondrial membranes (Mao et al., 2021).”