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

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.

A matter of new life and cell death: programmed cell death in the mammalian ovary

“…The discovery that ferroptosis is inhibited in granulosa cells from patients with PCOS via the circRHBG-miR-515-5p-SLC7A11 axis emphasizes the importance of PCD other than apoptosis in this disease and may provide new diagnostic molecular markers or therapeutic targets [ 214 ]. A recent report described an experimental attempt to treat PCOS in a mouse model by inducing ferroptosis [ 324 ]. The administration of n-3 PUFAs in the diet to dehydroepiandrosterone-treated mice activated Hippo signaling and YAP1 exocytosis, and suppressed NRF2, a protein that regulates critical ferroptosis-related genes ( GPX4 , GSS , TFRC , HMOX1 , and others) [ 325 ], leading to the promotion of ferroptosis in ovarian granulosa cells.…”

The mechanisms crosstalk and therapeutic opportunities between ferroptosis and ovary diseases

“…recently found that n-3 polyunsaturated fatty acids (n-3 PUFAs) can activate the Hippo signaling pathway, inhibit yes-associated protein 1 (YAP1) from entering the nucleus, weaken the interaction between YAP1 and Nrf2, and increase the sensitivity of ovarian GC to ferroptosis. As a result, GC can alleviate follicular development arrest caused by abnormal proliferation of GC ( 51 ). In summary, oxidative stress, mitochondrial dysfunction, and abnormal secretion of nutritional factors associated with ferroptosis in GC affect the growth and development of ovaries.…”