Lu Minghui, Han Yanli, Zhang Yu, Yu Ruijie, Su Yining, Chen Xueyao, Liu Boyang, Li Tao, Zhao Rusong, Zhao Han
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, China.
National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China.
Cell Prolif. 2025 Apr;58(4):e13780. doi: 10.1111/cpr.13780. Epub 2024 Dec 18.
Ageing of the endometrium is a critical factor that affects reproductive health, yet its intricate mechanisms remain poorly explored. In this study, we performed transcriptome profiling and experimental verification of endometrium and endometrial organoids from young and advanced age females, to elucidate the underlying mechanisms and to explore novel treatment strategies for endometrial ageing. First, we found that age-associated decline in endometrial functions including fibrosis and diminished receptivity, already exists in reproductive age. Subsequently, based on RNA-seq analysis, we identified several changes in molecular processes affected by age, including fibrosis, imbalanced inflammatory status including Th1 bias in secretory phase, cellular senescence and abnormal signalling transduction in key pathways, with all processes been further validated by molecular experiments. Finally, we uncovered for the first time that PI3K-AKT-FOXO1 signalling pathway is overactivated in ageing endometrium and is closely correlated with fibrosis and impaired receptivity characteristics of ageing endometrium. Blocking or activation of PI3K by LY294002 or 740Y-P could attenuate the effect of ageing or accelerate dysfunction of endometrial organoids. This discovery is expected to bring new breakthroughs for understanding the pathophysiological processes associated with endometrial ageing, as well as treatment strategies to improve reproductive outcomes in women of advanced reproductive age.
子宫内膜老化是影响生殖健康的关键因素，但其复杂机制仍未得到充分探索。在本研究中，我们对年轻和高龄女性的子宫内膜及子宫内膜类器官进行了转录组分析和实验验证，以阐明其潜在机制，并探索子宫内膜老化的新治疗策略。首先，我们发现与年龄相关的子宫内膜功能下降，包括纤维化和容受性降低，在育龄期就已存在。随后，基于RNA测序分析，我们确定了受年龄影响的分子过程中的一些变化，包括纤维化、分泌期Th1偏向等炎症状态失衡、细胞衰老以及关键途径中的异常信号转导，所有这些过程均通过分子实验进一步验证。最后，我们首次发现PI3K-AKT-FOXO1信号通路在老化子宫内膜中过度激活，且与老化子宫内膜的纤维化和容受性受损特征密切相关。用LY294002或740Y-P阻断或激活PI3K可减弱老化效应或加速子宫内膜类器官功能障碍。这一发现有望为理解与子宫内膜老化相关的病理生理过程带来新突破，以及为改善高龄育龄女性生殖结局提供治疗策略。
