Dhodh-KO Mouse

Dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in de novo pyrimidine nucleotide biosynthesis [3]. It plays a crucial role in maintaining normal cellular function as pyrimidine nucleotides are essential for DNA and RNA synthesis, cell cycle progression, and other key biological processes [4].

In cancer research, inactivation of DHODH has shown significant effects. In GPX4low cancer cells, it induces extensive mitochondrial lipid peroxidation and ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation [1]. Moreover, in glioblastoma, depletion of PRR11, which binds to and stabilizes DHODH, sensitizes GBM cells to temozolomide by inducing ferroptosis, indicating 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, inhibiting DNA and RNA synthesis, causing cell cycle arrest and death [4].

In conclusion, DHODH is essential for de novo pyrimidine nucleotide biosynthesis and normal cellular function. Its inactivation in various disease models, especially in cancer, reveals its potential as a therapeutic target. Studies on DHODH in cancer, such as in glioblastoma and T-cell acute lymphoblastic leukemia, suggest that targeting DHODH could offer new treatment strategies for these diseases [1,2,4].

References:

1. Mao, Chao, Liu, Xiaoguang, Zhang, Yilei, Olszewski, Kellen, Gan, Boyi. 2021. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. In Nature, 593, 586-590. doi:10.1038/s41586-021-03539-7. https://pubmed.ncbi.nlm.nih.gov/33981038/

2. Miao, Zong, Xu, Lei, Gu, Wei, Ji, Jing, Chen, Juxiang. 2024. A targetable PRR11-DHODH axis drives ferroptosis- and temozolomide-resistance in glioblastoma. In Redox biology, 73, 103220. doi:10.1016/j.redox.2024.103220. https://pubmed.ncbi.nlm.nih.gov/38838551/

3. Amos, Alvan, Amos, Alex, Wu, Lirong, Xia, He. 2023. The Warburg effect modulates DHODH role in ferroptosis: a review. In Cell communication and signaling : CCS, 21, 100. doi:10.1186/s12964-022-01025-9. https://pubmed.ncbi.nlm.nih.gov/37147673/

4. Sexauer, Amy N, Alexe, Gabriela, Gustafsson, Karin, Stegmaier, Kimberly, Sykes, David B. . DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia. In Blood advances, 7, 6685-6701. doi:10.1182/bloodadvances.2023010337. https://pubmed.ncbi.nlm.nih.gov/37648673/