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However, its molecular etiology and therapeutic options are still lacking. Here, leucine\u2010rich repeat containing 4 (LRRC4) is identified as a critical regulator of folliculogenesis expressed in granulosa cells (GCs), which contributes to ovarian reserve maintenance. LRRC4 deficiency triggers defective oocyte maturation and excessive follicular atresia through inhibition of GC differentiation and ultimately leads to POI. Mechanistically, LRRC4 balances mitochondrial fission and fusion to inhibit excessive mitophagy by promoting the K48\u2010linked ubiquitination degradation of Yes\u2010associated protein (YAP), thereby maintaining the metabolic homeostasis of mitochondrial aerobic respiration and glycolysis. Importantly, targeting LRRC4 normalized follicular development and ovarian function in POI model mice. In conclusion, these data reveal the novel pathogenesis of POI and suggest that LRRC4 is a potential target for the diagnosis and treatment of POI.<\/jats:p>","DOI":"10.1002\/advs.202417717","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T14:04:59Z","timestamp":1746194699000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells"],"prefix":"10.1002","volume":"12","author":[{"given":"Yujie","family":"Shang","sequence":"first","affiliation":[{"name":"The Affiliated Cancer Hospital of Xiangya School of Medicine Hunan Cancer Hospital Central South University  Changsha 410000 China"},{"name":"School of Chinese Medicine Hubei University of Chinese Medicine  Wuhan 430065 China"},{"name":"Hubei Shizhen Laboratory  Wuhan 430060 China"},{"name":"The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education Cancer Research Institute School of Basic Medicine Central South University  Changsha 410078 China"},{"name":"Affiliated Hospital of Hubei University of Chinese Medicine  Wuhan 430061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjun","family":"Li","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Hubei University of Chinese Medicine  Wuhan 430061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Han","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Henan University of Chinese Medicine  Zhengzhou 450003 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Deng","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education Cancer Research Institute School of Basic Medicine Central South University  Changsha 410078 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Gao","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education Cancer Research Institute School of Basic Medicine Central South University  Changsha 410078 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9766-9322","authenticated-orcid":false,"given":"Minghua","family":"Wu","sequence":"additional","affiliation":[{"name":"The Affiliated Cancer Hospital of Xiangya School of Medicine Hunan Cancer Hospital Central South University  Changsha 410000 China"},{"name":"The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education Cancer Research Institute School of Basic Medicine Central South University  Changsha 410078 China"},{"name":"Xiangya School of Public Health Central South University  Changsha 410013 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-024-00547-5"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/13697137.2019.1574738"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deac014"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jadohealth.2019.11.315"},{"key":"e_1_2_8_5_1","volume":"19","author":"Tong Y.","year":"2022","journal-title":"Int. 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