PMID- 38314939 OWN - NLM STAT- MEDLINE DCOM- 20240325 LR - 20240325 IS - 1613-4133 (Electronic) IS - 1613-4125 (Linking) VI - 68 IP - 5 DP - 2024 Mar TI - alpha-Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3-Mediated Pyroptosis of Granulosa Cells. PG - e2300784 LID - 10.1002/mnfr.202300784 [doi] AB - SCOPE: Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effect of alpha-ketoglutarate (AKG) on ovarian reserve function in POI rats and further explores the potential molecular mechanisms. METHODS AND RESULTS: POI rats are caused by administration of cyclophosphamide (CTX) to determine whether AKG has a protective effect. AKG treatment increases the ovarian index, maintains both serum hormone levels and follicle number, and improves the ovarian reserve function in POI rats, as evidence by increased the level of lactate and the expression of rate-limiting enzymes of glycolysis in the ovaries, additionally reduced the expression of NLRP3, Gasdermin D (GSDMD), Caspase-1, Interleukin-18 (IL-18), and Interleukin-1 beta (IL-1beta). In vitro, KGN cells are treated with LPS and nigericin to mimic pyroptosis, then treated with AKG and MCC950. AKG inhibits inflammatory and pyroptosis factors such as NLRP3, restores the glycolysis process in vitro, meanwhile inhibition of NLRP3 has the same effect. CONCLUSION: AKG ameliorates CTX-induced POI by inhibiting NLRP3-mediated pyroptosis, which provides a new therapeutic strategy and drug target for clinical POI patients. CI - (c) 2024 Wiley-VCH GmbH. FAU - Liu, Ke AU - Liu K AUID- ORCID: 0000-0001-6733-4046 AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. FAU - Wu, Yafei AU - Wu Y AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. FAU - Yang, Wenqin AU - Yang W AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. FAU - Li, Tianlong AU - Li T AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. FAU - Wang, Zhongxu AU - Wang Z AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. FAU - Xiao, Shu AU - Xiao S AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. FAU - Peng, Zhenghua AU - Peng Z AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. FAU - Li, Meng AU - Li M AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. FAU - Xiong, Wenhao AU - Xiong W AD - Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, Hunan, 421001, China. FAU - Li, Meixiang AU - Li M AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. FAU - Chen, Xi AU - Chen X AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. FAU - Zhang, Shun AU - Zhang S AD - Department of Reproductive Medical Center, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, China. FAU - Lei, Xiaocan AU - Lei X AD - Institute of Clinical Anatomy & Reproductive Medicine, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. LA - eng GR - 82101720/National Natural Science Foundation of China/ GR - 2020GXNSFAA297097/Natural Science Foundation of Guangxi in China/ GR - 2021JJ30021/Natural Science Foundation of Hunan Province/ GR - 20A434 20B501/Scientific Research Foundation of Hunan Provincial Education Department/ GR - QL20230239/Research and Innovation Program for Graduate Students of Hunan Province/ GR - X202110555521/National Training Program of Innovation and Entrepreneurship for Undergraduates/ PT - Journal Article DEP - 20240205 PL - Germany TA - Mol Nutr Food Res JT - Molecular nutrition & food research JID - 101231818 RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Ketoglutaric Acids) RN - 0 (Inflammasomes) SB - IM MH - Humans MH - Rats MH - Female MH - Animals MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Ketoglutaric Acids/pharmacology MH - *Primary Ovarian Insufficiency/chemically induced/drug therapy MH - *Ovarian Reserve MH - Pyroptosis MH - Granulosa Cells/metabolism MH - Inflammasomes/metabolism OTO - NOTNLM OT - alpha-ketoglutarate OT - granulosa cell OT - ovarian reserve OT - premature ovarian insufficiency OT - pyroptosis EDAT- 2024/02/05 14:44 MHDA- 2024/03/25 06:42 CRDT- 2024/02/05 08:56 PHST- 2023/12/14 00:00 [revised] PHST- 2023/11/07 00:00 [received] PHST- 2024/03/25 06:42 [medline] PHST- 2024/02/05 14:44 [pubmed] PHST- 2024/02/05 08:56 [entrez] AID - 10.1002/mnfr.202300784 [doi] PST - ppublish SO - Mol Nutr Food Res. 2024 Mar;68(5):e2300784. doi: 10.1002/mnfr.202300784. Epub 2024 Feb 5.