Unmasking the apoptotic potential of DHODH inhibition through targeting adaptive mitophagy (opens in new tab)

Targeting dihydroorotate dehydrogenase (DHODH) to restrict de novo pyrimidine synthesis is a promising anticancer strategy. However, the efficacy of DHODH inhibitors, such as brequinar (BQR), is often constrained by modest single-agent cytotoxicity, necessitating the exploration of combination therapies. Here, using mt-Keima-based mitophagy reporters and CRISPR/Cas9-mediated gene knockout models, we reveal a critical adaptive mechanism whereby BQR-induced mitochondrial reactive oxygen species...