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Ferroptosis, an iron\u2010dependent form of cell death driven by phospholipid peroxidation, has been implicated in various diseases. This study identifies significant\u00a0iron homeostasis\u00a0disorders and ferroptosis in PCOS patients with hyperandrogenemia, which is mediated by androgen\u2010induced reduction of ferritin heavy chain 1 (FTH1) protein levels in trophoblasts. Specifically, androgens upregulate FTH1 mRNA and protein synthesis by binding to androgen response elements on the FTH1 promoter via the androgen receptor (AR). Simultaneously, elevated androgen levels enhance chaperone\u2010mediated autophagy (CMA) through upregulating LAMP2A (lysosomal\u2010associated membrane protein 2), thereby promoting FTH1 protein degradation. When androgen levels are excessive or AR is overactivated, this CMA\u2010driven degradation exceeds FTH1 protein synthesis, leading to a reduction in FTH1 level. Furthermore, metformin was found to compete with androgens for AR binding, thereby stabilizing FTH1 and protecting trophoblasts from ferroptosis. In PCOS\u2010model mice, metformin significantly reduced early embryonic absorption. These findings reveal androgen\u2010induced ferroptosis as a key mechanism in placental dysfunction and highlight a potential application of metformin for treatment of early pregnancy loss associated with PCOS.<\/jats:p>","DOI":"10.1002\/advs.202506091","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T11:26:41Z","timestamp":1765884401000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hyperandrogenemia Induces Trophoblast Ferroptosis and Early Pregnancy Loss in Patients With PCOS via CMA\u2010Dependent FTH1 Degradation"],"prefix":"10.1002","volume":"13","author":[{"given":"Hanjing","family":"Zhou","sequence":"first","affiliation":[{"name":"Assisted Reproduction Unit Department of Obstetrics and Gynecology Sir Run Run Shaw Hospital School of Medicine Zhejiang University  Hangzhou 310016 China"},{"name":"Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility  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