Hydralazine Inhibits Cysteamine Dioxygenase to Treat Preeclampsia and Senesce Glioblastoma

Overview

Journal bioRxiv

Date 2025 Jan 13

PMID 39803451

Authors

Kyosuke Shishikura

Jiasong Li

Yiming Chen

Nate R McKnight

Katelyn A Bustin

Eric W Barr

Snehil R Chilkamari

Mahaa Ayub

Sun Woo Kim

Zongtao Lin

Ren-Ming Hu

Kelly Hicks

Xie Wang

Donald M ORourke

J Martin Bollinger

J Martin Bollinger Jr

Zev A Binder

William H Parsons

Kirill A Martemyanov

Aimin Liu

Megan L Matthews

Affiliations

Soon will be listed here.

Abstract

The vasodilator hydralazine (HYZ) has been used clinically for ~ 70 years and remains on the World Health Organization's List of Essential Medicines as a therapy for preeclampsia. Despite its longstanding use and the concomitant progress toward a general understanding of vasodilation, the target and mechanism of HYZ have remained unknown. We show that HYZ selectively targets 2-aminoethanethiol dioxygenase (ADO) by chelating its metal cofactor and alkylating one of its ligands. This covalent inactivation slows entry of proteins into the Cys/N-degron pathway that ADO initiates. HYZ's capacity to stabilize regulators of G-protein signaling (RGS4/5) normally marked for degradation by ADO explains its effect on blood vessel tension and comports with prior associations of insufficient RGS levels with human preeclampsia and analogous symptoms in mice. The established importance of ADO in glioblastoma led us to test HYZ in these cell types. Indeed, a single treatment induced senescence, suggesting a potential new HYZ-based therapy for this deadly brain cancer.

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