Science advances · 2025
Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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, Martin Bollinger J, Binder Zev A, Parsons William H, Martemyanov Kirill A, Liu Aimin, Matthews Megan L
Аннотация
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.