DHODH inhibitors sensitize cancer cells to ferroptosis via FSP1 inhibition

Abstract The quest for novel targets breaking cancer therapeutic resistance has led to exciting efforts to leverage ferroptosis specifically in cancer cells, traditionally vulnerable to iron-dependent lipid peroxidation 1 . In a recent paper published in this venue, Mao et al. 2 introduced mitochondrially localized dihydroorotate dehydrogenase (DHODH) as an enzyme mediating ferroptosis resistance in tumor cells by reducing mitochondrial ubiquinone (CoQ 10 ), which in turn facilitates scavenging of oxygen radicals in mitochondrial membranes.