Shi Weiwei, Lin Hao, Di Wu, He Cong, Shen Yang
Department of Obstetrics and Gynecology, Zhongda Hospital Affiliated to Southeast University, Nanjing, 210009, Jiangsu, China.
Department of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China.
Reprod Biol Endocrinol. 2025 Apr 26;23(1):61. doi: 10.1186/s12958-025-01396-x.
Polycystic ovary syndrome (PCOS) is a pivotal cause of anovulatory infertility and the pathogenesis remains elusive. Cellular senescence and sphingolipid metabolism disorder are closely intertwined, and both have been demonstrated present within the granulosa cells of PCOS, while research on the combined impact of senescence and sphingolipids on PCOS-related anovulation is scarce.
Here, we leveraged four datasets of PCOS and executed differential gene expression analysis, engaged in WGCNA, and harnessed machine learning algorithms-including RF, SVM-RFE, and LASSO-to deeply explore the key genes that interact with senescence and sphingolipid metabolism in granulosa cells of PCOS. These key genes were subjected to further analysis to construct a diagnostic model, forecast immune cell infiltration, and identify potential agents. Additionally, within the testosterone-stimulated granulosa cells, we validated the expression of key genes, confirmed senescence and sphingolipids dysregulation, and evaluated the therapeutic efficacy of the candidate agent.
Our research pinpointed a set of genes (LYN, PLCG2, STAT5B, MMP9, and IL6R) that showed promise as biomarkers for PCOS-related anovulation and the diagnostic nomogram was developed. These biomarkers were linked to various immune cell types infiltration. In testosterone-stimulated granulosa cells, we observed increased expression of these biomarkers, accompanied by signs of senescence and changes in sphingolipids. Importantly, the potential agent aspirin displayed the ability to ameliorate these two processes.
This study highlighted the important value of genes associated with senescence and sphingolipids dysregulation in PCOS. Aspirin targeting senescence could be a promising therapeutic drug for addressing anovulation associated with PCOS.
多囊卵巢综合征（PCOS）是无排卵性不孕症的一个关键原因，其发病机制仍不清楚。细胞衰老和鞘脂代谢紊乱密切相关，二者均已证实在PCOS的颗粒细胞中存在，而关于衰老和鞘脂对PCOS相关无排卵的联合影响的研究却很少。
在此，我们利用四个PCOS数据集进行差异基因表达分析、加权基因共表达网络分析（WGCNA），并利用机器学习算法（包括随机森林、支持向量机递归特征消除法和套索回归）深入探究在PCOS颗粒细胞中与衰老和鞘脂代谢相互作用的关键基因。对这些关键基因进行进一步分析以构建诊断模型、预测免疫细胞浸润并确定潜在药物。此外，在睾酮刺激的颗粒细胞中，我们验证了关键基因的表达，证实了衰老和鞘脂失调，并评估了候选药物的治疗效果。
我们的研究确定了一组基因（LYN、PLCG2、STAT5B、MMP9和IL6R），这些基因有望作为PCOS相关无排卵的生物标志物，并建立了诊断列线图。这些生物标志物与多种免疫细胞类型的浸润有关。在睾酮刺激的颗粒细胞中，我们观察到这些生物标志物的表达增加，同时伴有衰老迹象和鞘脂变化。重要的是，潜在药物阿司匹林显示出改善这两个过程的能力。
本研究突出了与PCOS中衰老和鞘脂失调相关基因的重要价值。靶向衰老的阿司匹林可能是治疗PCOS相关无排卵的一种有前景的治疗药物。
