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

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

doi:10.3390/nu15081927

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

Nutrients. 2023 Apr 16;15(8):1927. doi: 10.3390/nu15081927.

Authors

Peiwen Zhang^{1

2}, Yuheng Pan^{1

2}, Shuang Wu^{1

2}, Yuxu He^{1

2}, Jinyong Wang³, Lei Chen^{1

2}, Shunhua Zhang^{1

2}, Hui Zhang⁴, Ye Zhao^{1

2}, Lili Niu^{1

2}, Mailin Gan^{1

2}, Yan Wang^{1

2}, Linyuan Shen^{1

2}, Li Zhu^{1

2}

Affiliations

¹ 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.
² Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China.
³ Chongqing Academy of Animal Science, Chongqing 402460, China.
⁴ Sichaun Center for Animal Disease Control, Chengdu 610041, China.

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.

Keywords: PCOS; YAP1; ferroptosis; n-3 PUFA.

MeSH terms

Animals
Cell Proliferation
Female
Ferroptosis*
Hippo Signaling Pathway
Humans
Mice
NF-E2-Related Factor 2 / metabolism
Polycystic Ovary Syndrome* / metabolism
Quality of Life

Substances

NF-E2-Related Factor 2

Grants and funding

This work was supported by National Key Research and Development Program of China (2021YFD1200801), Sichuan Science and Technology Program (2021ZDZX0008, 2021YFYZ0007, scsztd-2023-08-09), China Agriculture Research System (CARS-pig-35), National Center of Technology Innovation for Pigs.