Dihydroorotate dehydrogenase: a multifunctional target in cancer, infectious diseases, and immune disorders.

Pyrimidine is required for the biosynthesis of DNA, RNA, glycoproteins, and phospholipids. Dihydroorotate dehydrogenase (DHODH) is a crucial flavin-dependent enzyme in mitochondria involved in the de novo pyrimidine synthesis and has been considered a significant drug target for diseases involving viral infections and parasitic diseases. Moreover, it has gained attention as a promising target for cancer treatment in recent years. This review introduces the structural and biochemical properties of DHODH and elaborates on its role in mitochondrial energy metabolism and ferroptosis. It summarizes the role of DHODH in cancer occurrence and development, as well as the in vivo effects and related regulatory mechanisms of DHODH inhibition. Moreover, it systematically discusses the latest developments in drug development based on the selective inhibition of DHODH, and introduces the therapeutic potential of DHODH inhibitors in cancer, bacterial and viral infections, and immune disorders.