Ferroptosis, a form of non-apoptotic cell death that is hallmarked by lipid peroxidation of cellular membranes, has gained considerable attention as it is considered a potential therapeutic target for breaking cancer therapeutic resistance 1. In their recent Article, Mao et al. 2 identified mitochondrially localized dihydroorotate dehydrogenase (DHODH) as an additional enzyme that mediates suppression of ferro ptosis, implying that inhibition of DHODH may present a promising strategy to overcome ferroptosis resistance in cancer cells. Here we show that the contribution of DHODH in ferroptosis suppression appears to be small and context-dependent, because the ferroptosis-sensitizing effect of DHODH inhibitors is apparent only at high concentrations that also efficiently inhibit ferroptosis-suppressor protein 1 (FSP1), which has an important role in ferroptosis defence 3. The observed effects on ferroptosis sensitization with this concentration of inhibitors cannot be attributed to DHODH inhibition per se. Thus, applying compounds that modulate ferroptosis at appropriate concentrations is mandatory to avoid off-target effects. Canonically, DHODH catalyses the ubiquinone (CoQ10)-dependent oxidation of dihydroorotate to orotate. Orotate is an essential building block for the de novo pyrimidine biosynthesis that is required during cell proliferation, and therefore DHODH presents a promising target for tumour therapy 4 (Extended Data Fig. 1a). Mao et al. 2 concluded that in addition to the mitochondrial form of glutathione peroxidase 4 (GPX4), DHODH is able to suppress ferroptosis at the inner mitochondrial membranes by reducing CoQ10 to ubiquinol. Ubiquinol in turn facilitates the scavenging of phospholipid radicals, which implies that DHODH may constitute a druggable target for ferroptosis sensitization 2. Substantiating their conclusions, the authors showed that cancer cell lines with genetic deletion of DHODH were more sensitive to ferroptosis-inducing agents, including the GPX4 inhibitor (1S, 3R)-RSL3 (RSL3). Moreover, they showed that brequinar, a potent and selective inhibitor of DHODH, also sensitized cancer cells towards ferroptosis. Although a comprehensive mechanistic framework explaining the molecular events that ultimately determine the cells’ sensitivity to ferroptosis is an important goal for the ferroptosis field, the study by Mao et al. 2 contains several weaknesses and misinterpretations, strongly arguing against the conclusion that inhibition of DHODH is a promising target to overcome ferroptosis resistance in cancer cells. First, the authors used extremely high concentrations of brequinar (500 μM), far exceeding the reported half-maximal inhibitory concentration (IC50) of 7 nM, to inhibit DHODH 4, 5. Although we could indeed observe a synergistic effect of brequinar and ferroptosis inducers, including RSL3, in various cancer cells (Fig. 1a and Extended Data