Dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in de novo pyrimidine nucleotide biosynthesis. It catalyzes the fourth step of this process, playing a crucial role in cell proliferation as pyrimidine nucleotides are essential for DNA and RNA synthesis. Besides its role in nucleotide synthesis, it is also involved in the defense against ferroptosis, an iron-dependent regulated cell death [1,3].

In cancer cells, inactivation of DHODH, especially in those with low GPX4 expression, induces extensive mitochondrial lipid peroxidation and ferroptosis [1]. In glioblastoma, depletion of PRR11, which directly binds to and stabilizes DHODH, sensitizes cells to temozolomide by inducing ferroptosis, suggesting a role of the PRR11-DHODH axis in ferroptosis-and temozolomide-resistance [2]. In T-cell acute lymphoblastic leukemia, small-molecule inhibition of DHODH leads to intracellular nucleotide starvation, cell cycle arrest, and cell death, with T lymphoblasts being specifically sensitive to this [4].

In conclusion, DHODH is essential for de novo pyrimidine nucleotide biosynthesis and has a significant role in cancer-related processes such as ferroptosis and drug resistance. Inhibiting DHODH shows promise as a therapeutic strategy in various cancers, including glioblastoma and T-cell acute lymphoblastic leukemia, by targeting its role in nucleotide metabolism and ferroptosis regulation.