Ferroptosis, a form of cell death caused by accumulation of peroxidized lipids, has emerged as an important process of tumour suppression. Two main mechanisms—involving GPX4 and FSP1—are known to control ferroptosis. Boyi Gan and colleagues now show that DHO dehydrogenase (DHODH) is also a regulator of ferroptosis. DHODH acts at the mitochondrial membrane to prevent mitochondrial lipid peroxidation, thereby suppressing ferroptosis. Mechanistically, DHODH acts as a back-up system for GPX4 to suppress ferroptosis through production of ubiquinol. Interestingly, this is the first demonstration that lipid peroxidation in mitochondria (in contrast to other reported sites) can induce ferroptosis. The authors also show that pharmaceutical DHODH inhibition triggers ferroptosis and suppresses the growth of tumours expressing low levels of GPX4, and cooperates with GPX4 inhibitors in tumours with high GPX4 expression.
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