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The addition of n-3 PUFA to the diet may slightly reduce body weight and greatly alleviate disturbed blood hormone levels in PCOS mice. We treated KGN as a cell model for n-3 PUFA addition and showed that n-3 PUFA inhibited the proliferation of GCs and promoted ferroptosis in ovarian granulosa cells. We used CCK-8, fluorescence quantitative transmission electron microscopy experiments and ferroptosis marker gene detection and other methods. Furthermore, n-3 PUFA was found to promote YAP1 exocytosis by activating Hippo and weakening the cross-talk between YAP1 and Nrf2 by activating the Hippo signaling pathway. In this study, we found that n-3 PUFA inhibited the over proliferation of granulosa cells in ovarian follicles by activating Hippo, promoting YAP1 exocytosis, weakening the cross-talk between YAP1 and Nrf2, and ultimately activating the ferroptosis sensitivity of ovarian granulosa cells. We demonstrate that n-3 PUFA can alleviate the hormonal and estrous cycle disorder with PCOS by inhibiting the YAP1-Nrf2 crosstalk that suppresses over proliferating ovarian granulosa cells and promotes iron death in GCs. These findings reveal the molecular mechanisms by which n-3 PUFA attenuates PCOS and identify YAP1-Nrf2 as a potential therapeutic target for regulation granulosa cells in PCOS.<\/jats:p>","DOI":"10.3390\/nu15081927","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T02:02:59Z","timestamp":1681696979000},"page":"1927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["n-3 PUFA Promotes Ferroptosis in PCOS GCs by Inhibiting YAP1 through Activation of the Hippo Pathway"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4637-4094","authenticated-orcid":false,"given":"Peiwen","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China"},{"name":"Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5366-9531","authenticated-orcid":false,"given":"Yuheng","family":"Pan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China"},{"name":"Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, 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and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China"},{"name":"Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China"},{"name":"Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Sichaun Center for Animal Disease Control, Chengdu 610041, 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Steroid Biochem. Mol. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Burnatowska, E., Wikarek, A., Oboza, P., Ogarek, N., Glinianowicz, M., Kocelak, P., and Olszanecka-Glinianowicz, M. (2023). Emotional Eating and Binge Eating Disorders and Night Eating Syndrome in Polycystic Ovary Syndrome-A Vicious Circle of Disease: A Systematic Review. Nutrients, 15.","DOI":"10.3390\/nu15020295"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s11154-016-9326-7","article-title":"Polycystic ovary syndrome (PCOS) and endocrine disrupting chemicals (EDCs)","volume":"16","author":"Palioura","year":"2015","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"808898","DOI":"10.3389\/fendo.2022.808898","article-title":"Life Modifications and PCOS: Old Story But New Tales","volume":"13","author":"Gu","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1093\/humupd\/dmv025","article-title":"Metformin and lifestyle modification in polycystic ovary syndrome: Systematic review and meta-analysis","volume":"21","author":"Naderpoor","year":"2015","journal-title":"Hum. Reprod. Update"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"667422","DOI":"10.3389\/fendo.2021.667422","article-title":"Central Regulation of PCOS: Abnormal Neuronal-Reproductive-Metabolic Circuits in PCOS Pathophysiology","volume":"12","author":"Liao","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1210\/endrev\/bnac001","article-title":"Deconstructing a Syndrome: Genomic Insights Into PCOS Causal Mechanisms and Classification","volume":"43","author":"Dapas","year":"2022","journal-title":"Endocr. Rev."},{"key":"ref_8","first-page":"558","article-title":"N-3 fatty acids as preventive and therapeutic agents in attenuating PCOS complications","volume":"18","author":"Salek","year":"2019","journal-title":"EXCLI J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1093\/advances\/nmab141","article-title":"Nutritional Supplements and Complementary Therapies in Polycystic Ovary Syndrome","volume":"13","author":"Alesi","year":"2022","journal-title":"Adv. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Barrea, L., Arnone, A., Annunziata, G., Muscogiuri, G., Laudisio, D., Salzano, C., Pugliese, G., Colao, A., and Savastano, S. (2019). Adherence to the Mediterranean Diet, Dietary Patterns and Body Composition in Women with Polycystic Ovary Syndrome (PCOS). Nutrients, 11.","DOI":"10.3390\/nu11102278"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0753-3322(02)00193-2","article-title":"Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies","volume":"56","author":"Tapiero","year":"2002","journal-title":"Biomed. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.nutres.2009.01.007","article-title":"Dietary omega-3 fatty acids differentially influence ova release and ovarian cyclooxygenase-1 and cyclooxygenase-2 expression in rats","volume":"29","author":"Broughton","year":"2009","journal-title":"Nutr. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41419-020-2298-2","article-title":"Ferroptosis: Past, present and future","volume":"11","author":"Li","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"110108","DOI":"10.1016\/j.biopha.2020.110108","article-title":"The emerging role of ferroptosis in inflammation","volume":"127","author":"Sun","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e20210518","DOI":"10.1084\/jem.20210518","article-title":"Ferroptosis in infection, inflammation, and immunity","volume":"218","author":"Chen","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.canlet.2020.02.015","article-title":"Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs","volume":"483","author":"Su","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1016\/j.cmet.2021.05.016","article-title":"Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects","volume":"33","author":"Dierge","year":"2021","journal-title":"Cell Metab."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chen, J., Zaal, E.A., Berkers, C.R., Ruijtenbeek, R., Garssen, J., and Redegeld, F.A. (2021). Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation. Cells, 10.","DOI":"10.3390\/cells10092287"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1111\/j.1471-4159.2008.05234.x","article-title":"Docosahexaenoic acid-dependent iron accumulation in oligodendroglia cells protects from hydrogen peroxide-induced damage","volume":"105","author":"Brand","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.pharmthera.2017.07.007","article-title":"Omega-3 polyunsaturated fatty acids as a treatment strategy for nonalcoholic fatty liver disease","volume":"181","author":"Jump","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1007\/s10815-018-1235-0","article-title":"Hippo signaling in the ovary and polycystic ovarian syndrome","volume":"35","author":"Maas","year":"2018","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1210\/endrev\/bnac013","article-title":"Hippo Signaling in the Ovary: Emerging Roles in Development, Fertility, and Disease","volume":"43","author":"Clark","year":"2022","journal-title":"Endocr. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lidaka, L., Bekere, L., Lazdane, G., Lazovska, M., Dzivite-Krisane, I., and Gailite, L. (2022). Role of Single Nucleotide Variants in the YAP1 Gene in Adolescents with Polycystic Ovary Syndrome. Biomedicines, 10.","DOI":"10.3390\/biomedicines10071688"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/s41419-021-04331-1","article-title":"A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis","volume":"12","author":"Yang","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.21037\/atm-21-4174","article-title":"Involvement of ferroptosis in the granulosa cells proliferation of PCOS through the circRHBG\/miR-515\/SLC7A11 axis","volume":"9","author":"Zhang","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1095\/biolreprod.111.095208","article-title":"Temporal differences in granulosa cell specification in the ovary reflect distinct follicle fates in mice","volume":"86","author":"Mork","year":"2012","journal-title":"Biol. Reprod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"111288","DOI":"10.1016\/j.mce.2021.111288","article-title":"A high-androgen microenvironment inhibits granulosa cell proliferation and alters cell identity","volume":"531","author":"McFee","year":"2021","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/nature17959","article-title":"Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury","volume":"534","author":"Tao","year":"2016","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"799663","DOI":"10.3389\/fgene.2021.799663","article-title":"Pathway-Based Analysis Revealed the Role of Keap1-Nrf2 Pathway and PI3K-Akt Pathway in Chinese Esophageal Squamous Cell Carcinoma Patients with Definitive Chemoradiotherapy","volume":"12","author":"Dai","year":"2021","journal-title":"Front. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e551","DOI":"10.1016\/j.ajog.2020.04.004","article-title":"A genome-wide association study of polycystic ovary syndrome identified from electronic health records","volume":"223","author":"Zhang","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1016943","DOI":"10.3389\/fnut.2022.1016943","article-title":"Associations between omega-3 fatty acids and insulin resistance and body composition in women with polycystic ovary syndrome","volume":"9","author":"Lu","year":"2022","journal-title":"Front. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1186\/s12967-020-02519-1","article-title":"Impact of different omega-3 fatty acid sources on lipid, hormonal, blood glucose, weight gain and histopathological damages profile in PCOS rat model","volume":"18","author":"Komal","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.jad.2018.05.027","article-title":"The influences of vitamin D and omega-3 co-supplementation on clinical, metabolic and genetic parameters in women with polycystic ovary syndrome","volume":"238","author":"Jamilian","year":"2018","journal-title":"J. Affect. Disord."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/8\/1927\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:16:58Z","timestamp":1760123818000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/8\/1927"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,16]]},"references-count":33,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["nu15081927"],"URL":"https:\/\/doi.org\/10.3390\/nu15081927","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,16]]}}}