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Inhibiting adenylate cyclase (AC), which participates in the function of disturbed endocrine factors such as follicle\u2010stimulating hormone (FSH), could be a novel therapeutic strategy to treat PCOS. In this study, a novel AC activity assay was established and used for high\u2010throughput screening of a Food and Drug Administration (FDA)\u2010approved drug library. Consequently, aspirin effectively inhibited the activity of AC in\u00a0vitro and reduced estrogen biosynthesis by inhibiting the expression of aromatase in human granulosa cells, a key enzyme that catalyzes the conversion of androgens into estrogens. Aspirin irreversibly inhibited the activity of AC subtypes and covalently bound to recombinant AC by binding to Lys350 and Lys426, which correspond to Lys938 and Lys1014 of full\u2010length AC2. Mechanistically, aspirin inhibited cAMP response element\u2010binding protein\u2010mediated aromatase expression by the AKT\/mammalian target of rapamycin (mTOR) signaling pathway. Furthermore, aspirin effectively alleviated PCOS symptoms in mouse models by decreasing androgen levels, lowering insulin levels, and reducing cystic follicles. These results revealed that aspirin is a potent inhibitor of ACs and a previously unrecognized role of ACs in estrogen biosynthesis. Therefore, aspirin warrants further investigation as a novel therapeutic agent in PCOS.<\/jats:p>","DOI":"10.1096\/fj.202403152r","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T08:49:12Z","timestamp":1749026952000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Aspirin Suppresses Aromatase\u2010Mediated Estrogen Biosynthesis to Alleviate Polycystic Ovary Syndrome by the Inhibition of Adenylate Cyclase"],"prefix":"10.1096","volume":"39","author":[{"given":"Xiao\u2010ke","family":"Shi","sequence":"first","affiliation":[{"name":"Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences  Chengdu China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010wen","family":"Sheng","sequence":"additional","affiliation":[{"name":"Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences  Chengdu China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u2010yi","family":"Cao","sequence":"additional","affiliation":[{"name":"Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences  Chengdu China"},{"name":"Department of Pharmacy Kunming Municipal Hospital of Traditional Chinese Medicine  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Shi","sequence":"additional","affiliation":[{"name":"Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010lin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-024-00511-3"},{"key":"e_1_2_11_3_1","first-page":"668","article-title":"Fetal Safety of Letrozole and Clomiphene Citrate for Ovulation Induction","volume":"29","author":"Forman R.","year":"2007","journal-title":"Journal of Obstetrics and Gynaecology"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp1514916"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph13070136"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12958-020-0566-8"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2011.11.002"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1677\/jme.0.0250035"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2021.4906"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1113684"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2011.10.006"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-019-00137-x"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1530\/rep.0.1210217"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2024.118279"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/jf3022817"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01605"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.114.120063"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-018-0971-4"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.35.65"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra052717"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(99)01310-3"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2017.03.011"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.977742"},{"issue":"1","key":"e_1_2_11_24_1","first-page":"185","article-title":"Establishment and Application of Screening Model of Adenylate Cyclase Inhibitor","volume":"27","author":"Shi X. 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