SEARCHOTHERobstetrics and gynecology, endocrinology

other·obstetrics and gynecology, endocrinology, preclinical research, nutrition, micronutrients·PMC10145554

n -3 PUFA Promotes Ferroptosis in PCOS GCs by Inhibiting YAP1 through Activation of the Hippo Pathway

Nutrients · 14 authors, 4 centres

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TL;DR

This preclinical study used a human granulosa cell line and a mouse model of polycystic ovary syndrome (PCOS) to investigate the molecular mechanisms of n-3 PUFA. It found that n-3 PUFA activated the Hippo pathway, inhibited YAP1 nuclear entry, and promoted ferroptosis in ovarian granulosa cells, suggesting a potential mechanism for its beneficial effects in PCOS.

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This preclinical study investigated the molecular mechanisms by which n-3 polyunsaturated fatty acids (PUFA) affect ovarian granulosa cells in polycystic ovary syndrome (PCOS). Using a KGN human granulosa cell line and a PCOS mouse model, researchers treated cells with n-3 PUFA and performed proliferation assays, ferroptosis marker detection, and pathway analysis. The central finding was that n-3 PUFA activated the Hippo signaling pathway, which inhibited the nuclear translocation of YAP1 and weakened its cross-talk with Nrf2. This cascade promoted ferroptosis in granulosa cells. In the mouse model, dietary n-3 PUFA addition slightly reduced body weight and alleviated hyperandrogenemia. The implications suggest that targeting the Hippo-YAP1-Nrf2-ferroptosis axis could be a novel therapeutic strategy for managing granulosa cell over-proliferation in PCOS.

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other

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obstetrics and gynecology

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ORIGINAL PAPER

PMC10145554

n -3 PUFA Promotes Ferroptosis in PCOS GCs by Inhibiting YAP1 through Activation of the Hippo Pathway

Nutrients

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ABSTRACT

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by hyperandrogenemia with multiple suspended sinus follicles, thickened cortical tissue, and excessive proliferation of ovarian granulosa cells that severely affects the fertility and quality of life of women. 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.

CITATION EXPORT

Peiwen Zhang, Yuheng Pan, Shuang Wu et al.. n-3 PUFA Promotes Ferroptosis in PCOS GCs by Inhibiting YAP1 through Activation of the Hippo Pathway. Nutrients. (2023). https://doi.org/10.3390/nu15081927

AUTHORS

14 · 4 CENTRES

Peiwen Zhang, Yuheng Pan, Shuang Wu, Yuxu He, Jinyong Wang, Lei Chen, Shunhua Zhang, Hui Zhang, Ye Zhao, Lili Niu, Mailin Gan, Yan Wang, Linyuan Shen, Li Zhu

1Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China; [email protected] (P.Z.); [email protected] (Y.P.); [email protected] (S.W.); [email protected] (Y.H.); [email protected] (L.C.); [email protected] (S.Z.); [email protected] (Y.Z.); [email protected] (L.N.); [email protected] (M.G.); [email protected] (L.Z.)
2Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
3Chongqing Academy of Animal Science, Chongqing 402460, China; [email protected]
4Sichaun Center for Animal Disease Control, Chengdu 610041, China; [email protected]

EDITOR / REVIEWER

James H. Swain, Carlo Agostoni