biostudies-literatureShishikura KNIDA NIH HHSNCI NIH HHSeadx7687https://www.ebi.ac.uk/biostudies/studies/S-EPMC12526720biostudies-literatureUnknown11(42)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, Science advancesHydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma.PMC12526720R37 CA285434DP1 DA051620R01 DA036596Kim SWMartemyanov KAHu RMLi JMartin Bollinger JShishikura KHicks KBinder ZALin ZKeeley TPBarr EWParsons WHAyub MO'Rourke DMChilkamari SRLiu AMatthews MLChen YBustin KAWang XMcKnight NRfalseHydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma.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, 2025-01-01T00:00:00Z2025 Oct2026-07-15T14:33:13.274Z2026-07-06T03:08:29.188ZS-EPMC125267204109188010.1126/sciadv.adx7687