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.
Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China.
Nutrients. 2023 Apr 16;15(8):1927. doi: 10.3390/nu15081927.
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 -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 -3 PUFA addition and showed that -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, -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 -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 -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 -3 PUFA attenuates PCOS and identify YAP1-Nrf2 as a potential therapeutic target for regulation granulosa cells in PCOS.
多囊卵巢综合征（PCOS）是一种内分泌疾病，其特征是高雄激素血症伴多个闭锁卵泡、皮质组织增厚和卵巢颗粒细胞过度增殖，严重影响女性的生育能力和生活质量。在饮食中添加 -3PUFA 可能会稍微减轻体重，并极大地缓解 PCOS 小鼠紊乱的血液激素水平。我们将 KGN 作为添加 -3PUFA 的细胞模型进行治疗，结果表明 -3PUFA 抑制了 GC 的增殖，并促进了卵巢颗粒细胞中的铁死亡。我们使用 CCK-8、荧光定量透射电子显微镜实验和铁死亡标记基因检测等方法进行研究。此外，我们发现 -3PUFA 通过激活 Hippo 促进 YAP1 外排，并通过激活 Hippo 信号通路削弱 YAP1 与 Nrf2 之间的串扰，从而促进 YAP1 外排。在这项研究中，我们发现 -3PUFA 通过激活 Hippo 抑制卵巢卵泡中颗粒细胞的过度增殖，促进 YAP1 外排，削弱 YAP1 与 Nrf2 之间的串扰，最终激活卵巢颗粒细胞的铁死亡敏感性。我们证明 -3PUFA 通过抑制抑制过度增殖的卵巢颗粒细胞并促进 GC 中铁死亡的 YAP1-Nrf2 串扰，可缓解 PCOS 的激素和发情周期紊乱。这些发现揭示了 -3PUFA 减轻 PCOS 的分子机制，并确定 YAP1-Nrf2 作为调节 PCOS 中颗粒细胞的潜在治疗靶点。
