Dihydroorotate Dehydrogenase in Mitochondrial Ferroptosis and Cancer Therapy

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Since the identification of dihydroorotate dehydrogenase (DHODH) as a mitochondrial suppressor of ferroptosis in 2021, increasing evidence has highlighted its role in linking nucleotide metabolism, redox regulation, and tumor progression. We conducted a comprehensive review of publications on DHODH, ferroptosis, and cancer. Relevant studies were analyzed to synthesize mechanistic insights, translational implications, and therapeutic perspectives. DHODH, a flavin-dependent mitochondrial enzyme catalyzing the oxidation of dihydroorotate to orotate, integrates pyrimidine biosynthesis with electron transport chain activity. Beyond its canonical metabolic role, DHODH regenerates ubiquinol (CoQ₁₀H₂) to suppress mitochondrial lipid peroxidation and ferroptosis. Elevated DHODH expression in colorectal, hepatocellular, breast, renal, and brain cancers correlates with poor prognosis, therapy resistance, and immune evasion. Pharmacological inhibition of DHODH disrupts pyrimidine synthesis and redox defense, sensitizing GPX4-low tumors to ferroptosis. Preclinical studies demonstrate synergy between DHODH inhibitors and chemotherapy, radiotherapy, or immune checkpoint blockade. Nanoparticle-based delivery systems enhance therapeutic efficacy by simultaneously targeting multiple ferroptosis defense arms while reducing toxicity. DHODH serves as both a metabolic and redox checkpoint in cancer, linking ferroptosis suppression to proliferation and immune escape. Targeting DHODH offers a promising strategy to dismantle cancer resilience, particularly in combination with ferroptosis inducers and immunotherapies. Future research should focus on biomarker-guided stratification, nanomedicine platforms, and clinical translation of DHODH inhibitors.