DHODH catalyzes the conversion of dihydroorotate to orotate using quinone as an electron acceptor, serving as the fourth enzymatic step in de novo pyrimidine biosynthesis 1. Located on the mitochondrial inner membrane, DHODH requires ubiquinone as its electron acceptor, linking pyrimidine metabolism directly to mitochondrial electron transport chain function 23. Beyond its canonical biosynthetic role, DHODH functions as a critical ferroptosis suppressor by reducing ubiquinone to ubiquinol, a lipid-soluble antioxidant that prevents mitochondrial lipid peroxidation independent of cytosolic antioxidant systems 45. DHODH also regulates tumor immunosuppression through O-GlcNAcylation of neuropilin-1, driving macropinocytosis and repressing MHC class II expression 6. DHODH inhibition emerges as a cancer-selective therapeutic strategy: in MYC-amplified medulloblastoma, DHODH inhibition induces pyrimidine starvation, c-Myc degradation, and apoptosis 1. In glioblastoma, DHODH stabilization confers ferroptosis and temozolomide resistance 7. Conversely, elevated DHODH-mediated orotic acid production exacerbates liver fibrosis in metabolic-associated steatohepatitis 8. These findings establish DHODH as a metabolic hub regulating cell death, immune evasion, and tissue pathology, with significant therapeutic potential across oncology and metabolic disease.