Ying Jia, Zhang Xuehong, Sun Xiaoyan, Meng Qingxia
Center of Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China.
State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China.
Reprod Sci. 2025 May 8. doi: 10.1007/s43032-025-01873-z.
This study aimed to investigate the role of fat mass and obesity-associated protein (FTO), an N6-methyladenosine (mA) demethylase, in ovarian aging by examining the effects of FTO downregulation on key biological processes in human ovarian granulosa cells (KGN), including proliferation, apoptosis regulation, senescence, and steroidogenic function. Stable FTO knockdown in KGN cells was achieved using lentivirus, complemented by modeling premature senescence with HO treatment. The biological functions, such as cell proliferation, apoptosis, aging, and sex hormone secretion, were assessed using RT-qPCR, WB, EdU staining, and ELISA, respectively. Silencing FTO significantly inhibited the proliferation of KGN cells, promoted apoptosis and senescence, and disrupted their endocrine function. These effects were consistent in the HO-induced senescence model. Our findings identify FTO as a critical regulator of ovarian homeostasis. Depletion of FTO impairs granulosa cell viability, accelerates senescence-related functional decline, and diminishes steroidogenic capacity through mA-mediated modulation of key biosynthetic enzymes. These insights highlight FTO as a potential therapeutic target for age-related ovarian dysfunction.
本研究旨在通过检测FTO下调对人卵巢颗粒细胞（KGN）关键生物学过程（包括增殖、凋亡调控、衰老和类固醇生成功能）的影响，来探究脂肪量和肥胖相关蛋白（FTO，一种N6-甲基腺苷（m6A）去甲基化酶）在卵巢衰老中的作用。使用慢病毒实现KGN细胞中FTO的稳定敲低，并通过HO处理模拟早衰进行补充。分别使用RT-qPCR、WB、EdU染色和ELISA评估细胞增殖、凋亡、衰老和性激素分泌等生物学功能。沉默FTO显著抑制KGN细胞的增殖，促进凋亡和衰老，并破坏其内分泌功能。在HO诱导的衰老模型中这些作用是一致的。我们的研究结果确定FTO是卵巢内稳态的关键调节因子。FTO的缺失损害颗粒细胞活力，加速衰老相关的功能衰退，并通过m6A介导的关键生物合成酶调节降低类固醇生成能力。这些见解突出了FTO作为年龄相关性卵巢功能障碍潜在治疗靶点的地位。
