EETs Reduction Contributes to Granulosa Cell Senescence and Endometriosis‐Associated Infertility via the PI3K/AKT/mTOR Signaling Pathway

作者：Xiang Lin, Weijia Gu, Xiaomei Tong, Mengru Lai, Yi Zhang, Na Liu, Xiaoying Jin, Chao Li, Dong Huang, Feng Zhou, Yongdong Dai, Songying Zhang · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202505656 · 被引用次数：7 · 研究领域：Endometriosis Research and Treatment、Apelin-related biomedical research、Ovarian function and disorders

We aimed to examine abnormal oxidative lipid levels and their related mechanisms in EM-associated infertility. Through liquid chromatography tandem mass spectrometry analysis, decreased levels of epoxyeicosatrienoic acids (EETs), which have antioxidant and anti-senescence effects are observed, in EM patient follicular fluid samples. EET levels are positively correlated with in vitro fertilization outcomes. Lower 14, 15-EET concentrations led to a decreased GC antioxidant capacity, reduced ATP production, reactive oxygen species (ROS) accumulation in oocytes, and abnormal cumulus-oocyte complex (COC) expansion, ultimately resulting in decreased fertility. Elevated soluble epoxide hydrolase (EPHX2) expression in EM-GCs is the main reason for EET reduction in EM follicular fluid. Inhibiting EPHX2 in vivo or in vitro can reverse these observed abnormalities by upregulating EETs. 14, 15-EET treatment alleviated GC senescence and improved fertility by inhibiting excessive PI3K/AKT/mTOR signaling pathway activation in EM-GCs, with BEZ-235-mediated inhibition of this pathway significantly alleviating ROS-induced cell senescence and abnormal COC expansion. Oxidative stress-induced decreased EZH2/H3K27Me3 histone methylation led to elevated EPHX2 expression patterns in EM-GCs. Decreased 14, 15-EET levels resulted in ROS accumulation, reduced EZH2 enzymatic activity, less EPHX2/H3K27Me3 histone methylation, and increased EPHX2 protein expression levels, which further reduced 14, 15-EET ...