Document Type
Article
Publication Date
10-15-2025
Abstract
Hydralazine (HYZ), a treatment for preeclampsia and hypertensive crisis, is listed by the World Health Organization as an essential medicine. Its mode of action has remained unknown through its seven decades of clinical use. Here, we identify 2-aminoethanethiol dioxygenase (ADO), a key mediator of targeted protein degradation, as a selective HYZ target. The drug chelates ADO's metallocofactor and can alkylate one of its ligands. The resultant inactivation stabilizes regulators of G protein signaling (RGS4 and RGS5) that ADO normally marks for proteolysis, explaining the drug's vasodilatory activity and comporting with observations of diminished RGS levels in both clinical preeclampsia and a mouse model thereof. Its inhibition of ADO suggested use of HYZ against glioblastoma (GBM); indeed, a single dose robustly senesces cultured GBM cells. By establishing ADO as a nexus for GBM and preeclampsia and connecting it to HYZ, the results create opportunities for directed tailoring of the old drug for new therapies.
Recommended Citation
Shishikura, Kyosuke; Li, Jiasong; Chen, Yiming; McKnight, Nate R.; Keeley, Thomas P.; Bustin, Katelyn A.; Barr, Eric W.; Chilkamari, Snehil R.; Ayub, Mahaa; Kim, Sun Woo; Lin, Zongtao; Hu, Ren-Ming; Hicks, Kelly; Wang, Xie; O'Rourke, Donald M.; Bollinger, J. Martin; Binder, Zev A.; Parsons, William H.; Martemyanov, Kirill A.; Liu, Aimin; and Matthews, Megan L., "Hydralazine Inhibits Cysteamine Dioxygenase to Treat Preeclampsia and Senesce Glioblastoma" (2025). SKMC Student Presentations and Publications. Paper 77.
https://jdc.jefferson.edu/skmcstudentworks/77
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Language
English
Included in
Cardiovascular Diseases Commons, Chemical Actions and Uses Commons, Enzymes and Coenzymes Commons, Female Urogenital Diseases and Pregnancy Complications Commons, Heterocyclic Compounds Commons
Comments
This article is the author’s final published version in Science Advances, Volume 11, Issue 42, 2025, Pages 1-17.
The published version is available at https://doi.org/10.1126/sciadv.adx7687. Copyright © 2025 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.