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An abnormally elevated production of placental testosterone (T<jats:sub>0<\/jats:sub>) has been documented in patients with early\u2010onset preeclamptic (E\u2010PE). However, the underlying mechanisms remain unclear. In this study, we found that E\u2010PE placentas exhibited significantly increased expressions of 3\u03b2\u2010HSD1 (3\u03b2\u2010Hydroxysteroid Dehydrogenase 1) and 17\u03b2\u2010HSD3 (17\u03b2\u2010Hydroxysteroid Dehydrogenase 3), the rate\u2010limiting enzymes for T<jats:sub>0<\/jats:sub> synthesis. This was strongly correlated with an elevated level of O\u2010linked N\u2010acetylglucosaminylation (O\u2010GlcNAcylation) of GATA3 (GATA binding protein 3). In human trophoblast cells, O\u2010linked\u2010N\u2010acetylglucosamine (O\u2010GlcNAc) modification of GATA3 on Thr<jats:sup>322<\/jats:sup> stabilized the protein and enhanced the transcriptional regulation of 3\u03b2\u2010HSD1 and 17\u03b2\u2010HSD3, thereby increasing T<jats:sub>0<\/jats:sub> production. Hypoxia, a well\u2010established pathological factor in PE, significantly enhanced the O\u2010GlcNAcylation of GATA3 in human trophoblast cells. Our findings suggest that hypoxia\u2010induced overactive O\u2010GlcNAcylation of GATA3 contributes to the exacerbated T<jats:sub>0<\/jats:sub> production in E\u2010PE placentas. These findings provide a new perspective on the pathogenesis of E\u2010PE from the standpoint of posttranslational regulation and may illuminate novel therapeutic strategies for adverse pregnancy outcomes such as E\u2010PE.<\/jats:p>","DOI":"10.1002\/mco2.70115","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T01:07:12Z","timestamp":1741741632000},"source":"Crossref","is-referenced-by-count":9,"title":["Hypoxia\u2010Induced O\u2010GlcNAcylation of GATA3 Leads to Excessive Testosterone Production in Preeclamptic Placentas"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1869-7865","authenticated-orcid":false,"given":"Juan","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology Key Laboratory of Organ Regeneration and Reconstruction Institute of Zoology Chinese Academy of Sciences  Beijing China"},{"name":"Beijing Center for Disease Prevention and 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