DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.

ABSTRACT: The ability of cancer cells to evade immune destruction is governed by various intrinsic factors including their metabolic state. Here we demonstrate that inactivation of dihydroorotate dehydrogenase (DHODH), a pyrimidine synthesis enzyme, increases cancer cell sensitivity to T cell cytotoxicity through induction of ferroptosis. Lipidomic and metabolomic analyses reveal that DHODH inhibition reduces CDP-choline level and attenuates the synthesis of phosphatidylcholine (PC) via the CDP-choline-dependent Kennedy pathway. To compensate this loss, there is increased synthesis from phosphatidylethanolamine via the phospholipid methylation pathway resulting in increased generation of very long chain polyunsaturated fatty acid-containing PCs. Importantly, inactivation of Dhodh in cancer cells pro

SUBMITTER: Teng D 

PROVIDER: S-EPMC12022163 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature