{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:46:57Z","timestamp":1791809217226,"version":"4.3.4"},"reference-count":23,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100006407","name":"Natural Science Foundation of Henan Province","doi-asserted-by":"publisher","award":["262300421646"],"award-info":[{"award-number":["262300421646"]}],"id":[{"id":"10.13039\/501100006407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,10,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Obesity triggers ovarian dysfunction and female infertility accompanied by granulosa cell damage. Ferroptosis, iron\u2010dependent lipid peroxidation\u2010mediated cell death, participates in multiple reproductive diseases, yet the molecular cascade linking metabolic obesity to granulosa ferroptosis remains undefined. Using high\u2010fat diet obese mice, primary human granulosa cells from obese infertile patients, and KGN cell lines, we identified the nuclear receptor NR4A1 as a key mediator of obesity\u2010induced ferroptosis downstream of PI3K\/AKT signaling. Elevated NR4A1 was associated with upregulated ACSL4 and suppressed GPX4, accompanied by iron overload, lipid peroxidation, and mitochondrial collapse, impairing folliculogenesis and oocyte quality. Metformin reduced NR4A1 activation in association with PI3K\/AKT signaling modulation, thereby attenuating ferroptotic injury and contributing to the restoration of ovarian function. In\u00a0vivo NR4A1 agonist administration attenuated the protective effects of metformin, while ovarian\u2010specific NR4A1 knockdown alleviated HFD\u2010triggered ovarian ferroptosis. Single\u2010cell RNA\u2010seq further suggested that metformin remodels oocyte redox and folliculogenic transcriptional networks. These findings support a role for the PI3K\/AKT\u2013NR4A1 signaling pathway in driving ferroptosis during obesity\u2010related ovarian dysfunction and suggest a potential anti\u2010ferroptotic mechanism of metformin in this context.<\/jats:p>","DOI":"10.1096\/fj.202603415r","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:51:42Z","timestamp":1790351502000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>NR4A1<\/scp>\n                    \u2010Driven Granulosa Cell Ferroptosis Contributes to Obesity\u2010Related Ovarian Dysfunction and Metformin\u2010Mediated Ovarian Protection"],"prefix":"10.1096","volume":"40","author":[{"given":"Huihui","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Reproductive Medicine The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"},{"name":"Henan Key Laboratory of Reproduction and Genetics The First 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