{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T17:50:17Z","timestamp":1790445017837,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T00:00:00Z","timestamp":1732233600000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Rep Immunol"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Gestational diabetes mellitus (GDM) significantly risks maternal and neonatal health. Circular RNAs (circRNAs) regulate various diseases but their role in GDM is unclear. We investigated the involvement of circ\u2010ADAM9 in GDM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed circ\u2010ADAM9 expression in GDM\u2010related microarray data (GSE182737) and measured its levels in the blood of GDM patients. In a high\u2010fat diet\u2010induced GDM mouse model, we inhibited circ\u2010ADAM9 expression and tracked blood glucose levels, serum insulin, lipid levels, placental apoptosis, and reactive oxygen species (ROS) levels. Pathological changes in pancreatic tissues and fetal outcomes were also examined. Molecular interactions were explored using bioinformatics tools and validated through luciferase assays, real\u2010time quantitative polymerase chain reaction (RT\u2010qPCR), and Western blotting in high glucose (HG)\u2010induced human trophoblast cells (HTR\u20108\/SVneo). We further investigated the involvement of circ\u2010ADAM9\/miR\u2010375\/FPR2 axis in HG\u2010induced injury in HTR\u20108\/SVneo cells by assessing cell viability, apoptosis, ROS production, and antioxidant levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both GDM patients and GDM\u2010induced mice exhibited a substantial upregulation of circ\u2010ADAM9. Knockdown of circ\u2010ADAM9 lowered blood glucose, alleviated insulin resistance, improved lipid metabolism, decreased placental apoptosis and ROS levels, and reduced pancreatic lesions in GDM mice. Circ\u2010ADAM9 downregulation also improved fetal viability, weight, and crown\u2010rump length. In HG\u2010induced HTR\u20108\/SVneo cells, circ\u2010ADAM9 overexpression and miR\u2010375 downregulation were evident. Overexpression of miR\u2010375 inhibited circ\u2010ADAM9 activity, substantiating their binding interaction. In GDM mice, circ\u2010ADAM9 deficiency restored miR\u2010375 expression. TargetScanHuman predicted and luciferase assays confirmed the miR\u2010375\u2010FPR2 interaction and elevated FPR2 levels in GDM mice were reduced by circ\u2010ADAM9 silencing. In HG\u2010induced HTR\u20108\/SVneo cells, circ\u2010ADAM9 knockdown restored cell viability, suppressed apoptosis and ROS levels, and enhanced antioxidant enzyme levels. These effects were reversed by miR\u2010375 inhibition or FPR2 overexpression, suggesting circ\u2010ADAM9 upregulates FPR2 expression by sponging miR\u2010375 and modulating the MAPK pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study is the first to demonstrate the expression and function of circ\u2010ADAM9 in the progression of GDM. Circ\u2010ADAM9 downregulation ameliorates insulin resistance and placental injury in GDM by modulating the miR\u2010375\/FPR2 axis and inactivating the MAPK pathway, which may offer a novel therapeutic target for the treatment of GDM.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aji.70017","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T09:28:25Z","timestamp":1732267705000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Circ\u2010ADAM9 Knockdown Reduces Insulin Resistance and Placental Injury in Diabetic Mice via MAPK Pathway Inactivation"],"prefix":"10.1111","volume":"92","author":[{"given":"Ai","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Gynecology The People's Hospital of Nanjing Medical University  Huai'an Jiangsu 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