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The accumulation of retrograde menstruation and recurrent bleeding fosters a high\u2010iron environment in ectopic lesions, triggering ferroptosis in ectopic endometrial stromal cells (EESCs), thereby hindering the establishment of endometriosis. However, abnormal EESCs demonstrate resistance to ferroptosis in high\u2010iron environments, promoting the progression of this disease. Here, novel findings on the accumulation of creatine, derived from endogenous synthesis, in both peritoneal fluid and EESCs of patients with endometriosis are presented. Creatine supplementation reduces cellular iron concentrations, mitigating oxidative stress and lipid peroxidation, thereby enhancing cell viability and preventing ferroptosis under high\u2010iron conditions. Utilizing the drug affinity\u2013responsive target stabilization (DARTS) assay, prion protein (PrP) as a potential creatine\u2010sensing protein is identified. Mechanistically, creatine binds to the active site of PrP, inhibits the conversion of trivalent iron to divalent iron, and decreases iron uptake, promoting the tolerance of EESCs to ferroptosis. This interaction contributes to the development of endometriosis. The novel association between creatine and ferroptosis provides valuable insights into the role of creatine in endometriosis progression and highlights its potential as a therapeutic target for endometriosis.<\/jats:p>","DOI":"10.1002\/advs.202403517","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T07:37:28Z","timestamp":1723189048000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Creatine Promotes Endometriosis by Inducing Ferroptosis Resistance via Suppression of PrP"],"prefix":"10.1002","volume":"11","author":[{"given":"Siman","family":"Chen","sequence":"first","affiliation":[{"name":"Laboratory for Reproductive Immunology Hospital of Obstetrics and Gynecology Fudan University  Shanghai 200090 P. R. 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