Nature: DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition

DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition.

Our most recent Nature article:

Mishima E, Nakamura T, Zheng J, Zhang W, Mourão ASD, Sennhenn P, Conrad M.

DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition

Helmholtz Munich | ©Claudia Dalke

Original publication:

DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition.

Mishima E, Nakamura T, Zheng J, Zhang W, Mourão ASD, Sennhenn P, Conrad M.

Nature. 2023 Jul;619(7968):E9-E18. doi: 10.1038/s41586-023-06269-0. Epub 2023 Jul 5.PMID: 37407687 No abstract available.

A previous report suggested that dihydroorotate dehydrogenase (DHODH) protects against mitochondrial damage and ferroptosis and therefore may present a targetable vulnerability in cancer (Mao et al. Nature 2021). Since these conclusions were mainly based on exceedingly high concentrations of the DHODH inhibitor brequinar (BQR) used throughout this study, we questioned these conclusions and now demonstrate that high concentrations of BQR (and other DHODH inhibitors) sensitize to ferroptosis via inhibition of ferroptosis suppressor protein-1 (FSP1) and not via DHODH. We further show that it is the short form of glutathione peroxidase 4 (GPX4) (and not the mitochondrial form) that is key in protecting against lipid peroxidation and ferroptosis. Our current study therefore reinforces the notion that properly controlled inhibitor concentrations are key before strong conclusions can be drawn (Mishima*, Nakamura*, Zheng* et al., Nature 2023)