Meng Wu, Qingqing Zhu, Jiaqiang Xiong, Weicheng Tang, Dan Chen, Liru Xue, Yourong Feng, Yun Dai, Tong Wu, Chuqing Wu, Yican Guo, Simin Wei, Yibao Huang, Peizhe Zheng, Yuting Li, Yuting Li, Yiqing Song, Ting Ding, Mingfu Wu, Z L Li, Yueguang Rong, Wenwen Wang, Yan Li, Yan Li, Jun Dai, Shixuan Wang, Jinjin Zhang
Recent studies have highlighted the crucial role of mechanical properties in the ovarian microenvironment for ovarian function. However, the mechanisms that cause ovarian matrix stiffening during aging remain incompletely understood. Here we utilized atomic force microscopy (AFM) to demonstrate that human ovarian matrix stiffness increases with aging and in pathophysiological conditions, such as chemotherapy-induced premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS) and ovarian endometriosis. By integrating proteomic analysis of human ovarian tissue with transcriptomic profiling of human ovarian fibroblasts, we identified that IL-11, which is elevated in aging ovaries of mice, rats and humans, activates fibroblasts to secrete extracellular matrix (ECM), thereby increasing ovarian matrix stiffness. Genetic deletion of Il11ra1 in mice mitigated the increase in ovarian matrix stiffness and the decline in ovarian function associated with aging, chemotherapy-induced POI and PCOS. Single-nuclei RNA sequencing (snRNA-seq) revealed that blocking Il11ra1 reduces the proportion of activated fibroblasts. Furthermore, administration of siIl11 nanoparticles to aged mice and rats enhanced fertility and reduced ovarian matrix stiffness. Together, these findings highlight the pro-inflammatory factor IL-11 in regulating ovarian matrix stiffness. We propose that anti-IL-11 therapy represents a promising translational strategy for delaying ovarian aging. The ovarian stroma becomes increasingly stiff with age, impairing ovarian function. The mechanisms that underlie this process are only partly understood. Here, the authors show that IL-11, which is elevated in aging ovaries of mice, rats and humans, activates fibroblasts to secrete extracellular matrix, increasing ovarian stiffness. Targeting IL-11 mitigates ovarian aging.