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Inadequate understanding of the ovulation drivers hinders PCOS intervention. Herein, we report that follicle stimulating hormone (FSH) controls follicular fluid (FF) glutamine levels to determine ovulation. Murine ovulation starts from FF-exposing granulosa cell (GC) apoptosis. FF glutamine, which decreases in pre-ovulation porcine FF, elevates in PCOS patients FF. High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal, metabolic, and morphologic PCOS traits. Mechanistically, follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine, which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway. FSH and glutamine inhibit the rapture of cultured murine follicles. Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO. These suggest that glutamine, FSH, and ASK1-JNK pathway are targetable to alleviate PCOS.<\/jats:p>","DOI":"10.1093\/procel\/pwad065","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T07:23:02Z","timestamp":1704266582000},"page":"512-529","source":"Crossref","is-referenced-by-count":40,"title":["Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation"],"prefix":"10.1093","volume":"15","author":[{"given":"Kai-Hui","family":"Zhang","sequence":"first","affiliation":[{"name":"The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University , Shanghai 200090 , China"},{"name":"Shanghai Key Laboratory of Metabolic Remodeling, and Children\u2019s Hospital of Fudan University , Shanghai 200032 , China"},{"name":"Pediatric Research Institute, Children\u2019s Hospital Affiliated to Shandong University (Jinan Children\u2019s Hospital) , Jinan 250022 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei-Fei","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University , Shanghai 200090 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Ling","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University , Shanghai 200090 , China"},{"name":"Shanghai Key Laboratory of Metabolic Remodeling, and Children\u2019s Hospital of Fudan University , Shanghai 200032 , China"},{"name":"School of Life Sciences and Institutes of Biomedical Sciences , Fudan University, Shanghai 200438 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke-Fei","family":"Fang","sequence":"additional","affiliation":[{"name":"The Obstetrics & Gynecology 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