{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T14:50:52Z","timestamp":1781967052438,"version":"3.54.5"},"reference-count":27,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Rep Immunol"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Problem<\/jats:title>\n                    <jats:p>Preeclampsia (PE), characterized by hypertension and proteinuria, involves placental dysfunction linked to oxidative stress and ferroptosis. The role of estrogen receptor \u03b1 (ER\u03b1) in hypoxia\u2010induced trophoblast ferroptosis remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method of Study<\/jats:title>\n                    <jats:p>A PE rat model was established using L\u2010NAME injection. Placental tissues were analyzed for protein expression via Western blot. In vitro, HTR\u20108\/SVneo cells were cultured under hypoxic conditions to simulate PE\u2010related hypoxia. ER\u03b1 was knocked down using siRNAs, and acyl\u2010CoA synthetase long\u2010chain family member 4 (ACSL4) was overexpressed via plasmid transfection. Cell viability, apoptosis, migration, oxidative stress parameters, and ferroptosis\u2010related indicators were assessed using CCK\u20108, flow cytometry, Transwell assays, and specific biochemical kits. In addition, primary syncytiotrophoblast (STB) cells were isolated from placentas of healthy and PE rats for validation experiments. The transcriptional regulation of ACSL4 by ER\u03b1 was examined using dual luciferase reporter assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In PE rat placentas, ER\u03b1 and ACSL4 were significantly upregulated, while GPX4 and SLC7A11 were downregulated. In addition, the lipid peroxidation products 4\u2010HNE and MDA were significantly increased in PE placental tissues. Hypoxia induced ferroptosis in HTR\u20108\/SVneo cells, characterized by increased Fe\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      levels, elevated 4\u2010HNE and MDA levels, lipid peroxidation, and activation of the ER\u03b1\/ACSL4 axis. Knockdown of ER\u03b1 attenuated hypoxia\u2010induced cell injury, oxidative stress, and ferroptosis, whereas ACSL4 overexpression reversed these protective effects. Furthermore, experiments in primary STB cells isolated from PE rats showed that ER\u03b1 knockdown similarly alleviated ferroptosis\u2010associated injury and suppressed ACSL4 expression. Mechanistically, ER\u03b1 bound directly to the ACSL4 promoter and transcriptionally activated its expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The ER\u03b1\u2010ACSL4 axis plays a critical role in hypoxia\u2010induced ferroptosis in placental trophoblasts. ER\u03b1 transcriptionally activates ACSL4, promoting lipid peroxidation and ferroptosis, thereby contributing to placental dysfunction in PE. These findings provide a novel theoretical basis for understanding PE pathogenesis and highlight potential therapeutic targets for intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/aji.70258","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T15:19:11Z","timestamp":1779290351000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ER\u03b1 Facilitates Hypoxia\u2010induced Ferroptosis in Placental Trophoblasts by Transcriptionally Activating ACSL4"],"prefix":"10.1111","volume":"95","author":[{"given":"Xufei","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Obstetrics Jinhua Maternal and Child Health Care Hospital  Jinhua City Zhejiang Province China"},{"name":"Department of Obstetrics Women's Hospital Zhejiang University School  Hangzhou Zhejiang Province China"},{"name":"Jinhua's Key Laboratory of Birth Defects Prevention and Treatment  Jinhua Zhejiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Jinhua Maternal and Child Health Care Hospital  Jinhua City Zhejiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Jinhua Maternal and Child Health Care Hospital  Jinhua City Zhejiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5924-1091","authenticated-orcid":false,"given":"Lichao","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Jinhua Maternal and Child Health Care Hospital  Jinhua City Zhejiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9981-8583","authenticated-orcid":false,"given":"Min","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Jinhua Maternal and Child Health Care Hospital  Jinhua City Zhejiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Women's Hospital Zhejiang University School  Hangzhou Zhejiang Province 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