{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T07:45:15Z","timestamp":1791791115191,"version":"4.3.4"},"reference-count":29,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Gestational diabetes mellitus (GDM) is a common metabolic disorder during pregnancy. Metformin (MET) has emerged as a promising alternative to insulin, but its mechanism of action in the placenta remains incompletely understood. In this study, we aimed to examine whether MET counteracts high\u2010glucose\u2010induced ferroptosis by regulating activating transcription factor 2 (ATF2) and to delineate the underlying molecular mechanism in GDM. We established in\u00a0vitro GDM cell models using HTR\u20108\/SVneo trophoblast cells and an in\u00a0vivo STZ\u2010induced hyperglycemic rat model, followed by treatments including ATF2 lentiviral manipulation and MET administration. We evaluated cell viability, ferroptosis markers (ROS, MDA, GSH, iron deposition), and PI3K\/Akt signaling pathway activity. Our results demonstrated that in GDM patients and high\u2010glucose\u2010challenged HTR\u20108\/SVneo cells, MET promoted cell viability by suppressing ATF2, reactivating PI3K\/Akt signaling, enhancing nuclear Nrf2 translocation, and upregulating GPX4, while concurrently lowering ROS and MDA levels, elevating GSH, and reducing iron deposition. These protective effects were reversed by ATF2 overexpression or pathway inhibitors. In STZ\u2010induced hyperglycemic rats, MET decreased placental ATF2 expression, restored the PI3K\/Akt\u2010Nrf2\u2010GPX4 axis, alleviated ferroptosis, and reduced fetal weight. Collectively, our findings indicate that MET suppresses ATF2, activates PI3K\/Akt, drives Nrf2 nuclear import, upregulates GPX4, and curbs high\u2010glucose\u2010induced trophoblast ferroptosis, offering new mechanistic insight and therapeutic avenues for GDM.<\/jats:p>","DOI":"10.1096\/fj.202602249rr","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:36:14Z","timestamp":1790163374000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin Inhibits Trophoblast Ferroptosis by Suppressing\n                    <scp>ATF2<\/scp>\n                    and Activating the\n                    <scp>PI3K<\/scp>\n                    \/Akt\/Nrf2 Pathway to Improve Gestational Diabetes Mellitus"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0371-8394","authenticated-orcid":false,"given":"Dandan","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Changzhou Jiangsu China"},{"name":"Changzhou Key Laboratory of Maternal and Child Health Medicine  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9560-5639","authenticated-orcid":false,"given":"Yuhui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Changzhou Jiangsu China"},{"name":"Changzhou Key Laboratory of Maternal and Child Health Medicine  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9288-2819","authenticated-orcid":false,"given":"Wenjie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Changzhou Jiangsu China"},{"name":"Changzhou Key Laboratory of Maternal and Child Health Medicine  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3861-468X","authenticated-orcid":false,"given":"Siyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Changzhou Jiangsu China"},{"name":"Changzhou Key Laboratory of Maternal and Child Health Medicine  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2492-4489","authenticated-orcid":false,"given":"Chenying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Changzhou Jiangsu China"},{"name":"Changzhou Key Laboratory of Maternal and Child Health Medicine  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0321-6719","authenticated-orcid":false,"given":"Guangtong","family":"She","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Changzhou Jiangsu China"},{"name":"Changzhou Key Laboratory of Maternal and Child Health Medicine  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9622-3377","authenticated-orcid":false,"given":"Huiyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Changzhou Jiangsu China"},{"name":"Changzhou Key Laboratory of Maternal and Child Health Medicine  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26052320"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-59442-6"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19113342"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2024"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-021-02933-5"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56344-5"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-024-05009-w"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2024.115960"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.70115"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2024.05.011"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2024.2264"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1177547"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.115141"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1083838"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0000000000005640"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-023-02980-x"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0000000000005705"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/14767058.2023.2295809"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2021.04.229"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14589"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.01.033"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2022.11573"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.10.005"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2023.175967"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12890-023-02655-6"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2022.113615"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2025.111263"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2025.119800"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-024-01028-x"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202602249RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202602249RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202602249RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T06:52:23Z","timestamp":1791787943000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202602249RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":29,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2026,9,30]]}},"alternative-id":["10.1096\/fj.202602249RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202602249rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]},"assertion":[{"value":"2026-05-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e72333"}}