Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine nucleotide biosynthesis pathway [2,4,5]. It catalyzes the fourth step in this pathway, and its function is crucial for the synthesis of pyrimidine nucleotides, which are essential for DNA and RNA synthesis, thus playing a vital role in cell proliferation and survival [5].

In cancer research, inactivation of DHODH in GPX4low cancer cells induces extensive mitochondrial lipid peroxidation and ferroptosis, and it synergizes with ferroptosis inducers in GPX4high cancer cells [1]. DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane [1]. In glioblastoma, proline rich protein 11 (PRR11) directly binds to and stabilizes DHODH, leading to ferroptosis-resistant glioma in a DHODH-dependent manner [3]. In T-cell acute lymphoblastic leukemia, small molecule inhibition of DHODH leads to intracellular nucleotide starvation, inhibiting DNA and RNA synthesis, cell cycle arrest, and cell death [5].

In conclusion, DHODH is essential for de novo pyrimidine nucleotide biosynthesis. Research on DHODH, especially through gene inactivation in cancer cells, has revealed its role in ferroptosis defense in cancer, making it a potential therapeutic target in various cancers such as glioblastoma and T-cell acute lymphoblastic leukemia [1,3,5].

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. Froes, Thamires Quadros, Zapata, Luana Carlos Campisano, Akamine, Juliana Sayuri, Castilho, Marcelo Santos, Nonato, Maria Cristina. . DHODH Hot Spots: An Underexplored Source to Guide Drug Development Efforts. In Current topics in medicinal chemistry, 21, 2134-2154. doi:10.2174/1568026621666210804122320. https://pubmed.ncbi.nlm.nih.gov/34348625/

3. 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/

4. 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/

5. 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/