Qu Junjie, Qiu Meiting, Wang Jingyun, Chen Zhiqin, Chen Miaoxin, Teng Xiaoming, Li Yiran
Department of Reproductive Medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
Front Cell Dev Biol. 2025 Aug 29;13:1626938. doi: 10.3389/fcell.2025.1626938. eCollection 2025.
FGF19, an endocrine hormone, participating in ovarian function. This study investigated the roles of FGF19 in polycystic ovary syndrome (PCOS) and its associated molecular mechanisms, specifically focusing on the FGFR4-ERK-NRF2 pathway.
Clinical samples were collected to determine FGF19 levels, and proteomic analysis was performed on follicular fluid. A mouse model was established to investigate the molecular pathogenesis of PCOS. Subsequently, a series of experiments explored the effects and mechanisms of FGF19 on PCOS with and without oxidative stress.
Proteomics identified 144 differentially expressed proteins enriched in pathways including VEGF, PPAR, IL-2-STAT5, mTORC1, epithelial-mesenchymal transition, bile acid metabolism, and oxidative phosphorylation. FGF19/FGF15 levels were significantly higher in PCOS patients and mice compared to controls. In PCOS mice, FGFR4, NRF2, and HO1 were upregulated, while p-ERK/ERK levels were decreased. FGF19 overexpression promoted KGN cells viability while inhibiting apoptosis, upregulating FGFR4, NRF2, HO1, BCL2, and p-ERK/ERK, and downregulating BAX. However, LY3214996 reversed the action of FGF19 overexpression in KGN cells. H2O2 treatment decreased KGN cell viability, increased apoptosis, and elevated ROS levels. NRF2 knockdown further aggravated H2O2's effectd, whereas FGF19 overexpression countered the changes in viability, apoptosis, and ROS levels caused by H2O2. Furthermore, H2O2 stimulation upregulated BAX, NRF2, and HO1, while decreasing BCL2 and p-ERK/ERK levels; NRF2 knockdown further upregulated BAX and downregulated BCL2 and p-ERK/ERK. Conversely, FGF19 overexpression had opposite effects on NRF2 knockdown.
FGF19 may be involved in PCOS occurrence and development through the regulation of the FGFR4-ERK-NRF2 pathway.
成纤维细胞生长因子19（FGF19）作为一种内分泌激素，参与卵巢功能调节。本研究旨在探讨FGF19在多囊卵巢综合征（PCOS）中的作用及其相关分子机制，特别关注FGFR4-ERK-NRF2通路。
收集临床样本以测定FGF19水平，并对卵泡液进行蛋白质组学分析。建立小鼠模型以研究PCOS的分子发病机制。随后，进行了一系列实验，探讨FGF19在有无氧化应激情况下对PCOS的影响及机制。
蛋白质组学鉴定出144种差异表达蛋白，这些蛋白富集于包括血管内皮生长因子（VEGF）、过氧化物酶体增殖物激活受体（PPAR）、白细胞介素-2-信号转导子和转录激活子5（IL-2-STAT5）、哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）、上皮-间质转化、胆汁酸代谢及氧化磷酸化等通路中。与对照组相比，PCOS患者和小鼠体内的FGF19/FGF15水平显著升高。在PCOS小鼠中，FGFR4、NRF2和血红素氧合酶1（HO1）上调，而磷酸化细胞外信号调节激酶（p-ERK）/细胞外信号调节激酶（ERK）水平降低。FGF19过表达促进KGN细胞活力，同时抑制细胞凋亡，上调FGFR4、NRF2、HO1、B细胞淋巴瘤/白血病-2（BCL2）和p-ERK/ERK，下调Bcl-2相关X蛋白（BAX）。然而，LY3214996可逆转FGF19过表达在KGN细胞中的作用。过氧化氢（H2O2）处理降低了KGN细胞活力，增加了细胞凋亡，并提高了活性氧（ROS）水平。NRF2基因敲低进一步加重了H2O2的作用，而FGF过表达则抵消了H2O2引起的细胞活力、细胞凋亡和ROS水平的变化。此外，H2O2刺激上调了BAX、NRF2和HO1，同时降低了BCL2和p-ERK/ERK水平；NRF2基因敲低进一步上调了BAX，下调了BCL2和p-ERK/ERK。相反，FGF19过表达对NRF2基因敲低有相反的作用。
FGF19可能通过调节FGFR4-ERK-NRF2通路参与PCOS的发生发展。
