PXD067316

PXD067316 is an original dataset announced via ProteomeXchange.

Title	Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma
Description	Many safe and effective drugs have unknown targets, limiting opportunities to extend their use to other disease states with overlapping etiologies. Here, we have elucidated the mechanism of action of the direct vasodilator, hydralazine (HYZ), which has been used for more than seven decades and remains on the World Health Organization's List of Essential Medicines as a treatment for preeclampsia and hypertensive crisis. Using our chemoproteomic drug de-orphanization approach, we identify a key enzyme mediator of targeted protein degradation, 2-aminoethanethiol dioxygenase (ADO), as a selective HYZ target. The structure of the ADO•HYZ complex shows that the drug chelates the enzyme's metal cofactor in the course of alkylating one of its ligands. The resultant inactivation stabilizes regulators of G-protein signaling (RGS4/5) that are normally marked for degradation by ADO. This activity explains the drug's impact on blood vessel tension, and it comports with prior associations of insufficient RGS levels with both clinical preeclampsia and analogous symptoms in mice. The established importance of ADO in glioblastoma motivated evaluation of the efficacy of HYZ against such cells, revealing that a single dose induces prolonged senescence. The results identify ADO as a novel pharmacological target for both diseases and connect it to a known drug, opening avenues for the rational tailoring of HYZ to create new pharmaceuticals.
HostingRepository	PRIDE
AnnounceDate	2025-10-24
AnnouncementXML	Submission_2025-10-24_00:04:37.438.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD067316
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Kyosuke Shishikura
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-13 13:03:11	ID requested
⏵ 1	2025-10-24 00:04:38	announced

10.6019/PXD067316;

10.1126/SCIADV.ADX7687;

submitter keyword: glioblastoma, hydralazine,LC-MS, preeclampsia, mechanisms of action

Megan L. Matthews
contact affiliation	Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA
contact email	megamatt@sas.upenn.edu
lab head
Kyosuke Shishikura
contact affiliation	University of Pennsylvania
contact email	kyosuke@sas.upenn.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067316
     1. Label: PRIDE project
     2. Name: Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma