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GPR39, a G protein\u2010coupled receptor, has emerged as a possible therapeutic target, and its agonist, TC\u2010G 1008, may provide protection against metabolic disorders. In this study, we investigated the expression of GPR39 in the murine placenta and its role in GDM\u2010related placental dysfunction using a high\u2010fat diet\u2010induced GDM mouse model. Mice were treated with TC\u2010G 1008 (7.5 and 15\u2009mg\/kg) from gestational day 0 to 18, and placental tissues were analysed via RT\u2010PCR, Western blot, immunohistochemistry, ELISA, and biochemical assays. Our findings indicated that GPR39 expression was markedly reduced in GDM mice relative to wild\u2010type controls. Administration of TC\u2010G 1008 (7.5 and 15\u2009mg\/kg) enhanced fetal outcomes, including survival rate, weight, and crown\u2010rump length, while also mitigating maternal metabolic disorders such as hyperglycaemia, insulin resistance, and dyslipidaemia. Moreover, the administration of TC\u2010G 1008 mitigated placental oxidative stress by augmenting SOD activity and GSH levels, while inhibiting NLRP1 inflammasome activation, as shown by diminished expression of NLRP1, ASC, and Caspase\u20101, alongside lowered levels of IL\u20101\u03b2 and IL\u201018. Furthermore, GPR39 activation suppressed the NF\u2010\u03baB and MAPK signalling pathways. These findings suggest that GPR39 activation by TC\u2010G 1008 ameliorates placental dysfunction in GDM by mitigating oxidative stress and inflammation via suppression of the NLRP1 inflammasome, highlighting its potential as a therapeutic strategy for GDM\u2010associated complications.<\/jats:p>","DOI":"10.1111\/1440-1681.70074","type":"journal-article","created":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T08:24:47Z","timestamp":1758356687000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Activation of <scp>GPR39<\/scp> Ameliorates Placental Dysfunction by Inhibiting Activation of <scp>NLRP1<\/scp> Inflammasome in Gestational Diabetes Mellitus"],"prefix":"10.1111","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2907-5283","authenticated-orcid":false,"given":"Xiaohua","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Obstetrics Beijing Haidian Maternal &amp; Child 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