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Peer-reviewedCC BY-NC-NDNature Aging

Modulating IL-11-dependent matrix stiffness to delay ovarian aging

  • Meng Wu1,2,3
  • Qingqing Zhu1,2,3
  • Jiaqiang Xiong4
  • Weicheng Tang1,2,3
  • Dan Chen1,2,3
  • Liru Xue1,2,3
  • Yourong Feng1,2,3
  • Yun Dai1,2,3
  • Tong Wu1,2,3
  • Chuqing Wu1,2,3
  • Yican Guo1,2,3
  • Simin Wei1,2,3
13 more authors
  • Yibao Huang1,2,3
  • Peizhe Zheng1,2,3
  • Yuting Li1,5,2,6,3,7
  • Yiqing Song1,2,3
  • 丁婷1,2,3
  • Mingfu Wu1,2,3
  • Zifu Li8
  • 荣岳光9
  • Wenwen Wang10,11,12
  • Yan Li1,5,2,6,3,7
  • Jun Yan Dai13,14,15
  • Shixuan Wang16,17,18
  • Jinjin Zhang19,20,21
21 affiliations
  1. 1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  2. 2Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
  3. 3National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
  4. 4Department of Obstetrics and Gynecology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
  5. 5Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected]
  6. 6Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China. [email protected]
  7. 7National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China. [email protected]
  8. 8National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
  9. 9School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, Hubei, China
  10. 10Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected]
  11. 11Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China. [email protected]
  12. 12National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China. [email protected]
  13. 13Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected]
  14. 14Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China. [email protected]
  15. 15National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China. [email protected]
  16. 16Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected]
  17. 17Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China. [email protected]
  18. 18National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China. [email protected]
  19. 19Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected]
  20. 20Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China. [email protected]
  21. 21National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China. [email protected]
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{wu2026modulating,
  title = {{Modulating IL-11-dependent matrix stiffness to delay ovarian aging}},
  author = {Meng Wu and Qingqing Zhu and Jiaqiang Xiong and Weicheng Tang and Dan Chen and Liru Xue and Yourong Feng and Yun Dai and Tong Wu and Chuqing Wu and Yican Guo and Simin Wei and Yibao Huang and Peizhe Zheng and Yuting Li and Yiqing Song and 丁婷 and Mingfu Wu and Zifu Li and 荣岳光 and Wenwen Wang and Yan Li and Jun Yan Dai and Shixuan Wang and Jinjin Zhang},
  journal = {Nature Aging},
  year = {2026},
  month = jul,
  doi = {10.1038/s43587-026-01159-2},
  url = {https://doi.org/10.1038/s43587-026-01159-2},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Modulating IL-11-dependent matrix stiffness to delay ovarian aging
AU  - Meng Wu
AU  - Qingqing Zhu
AU  - Jiaqiang Xiong
AU  - Weicheng Tang
AU  - Dan Chen
AU  - Liru Xue
AU  - Yourong Feng
AU  - Yun Dai
AU  - Tong Wu
AU  - Chuqing Wu
AU  - Yican Guo
AU  - Simin Wei
AU  - Yibao Huang
AU  - Peizhe Zheng
AU  - Yuting Li
AU  - Yiqing Song
AU  - 丁婷
AU  - Mingfu Wu
AU  - Zifu Li
AU  - 荣岳光
AU  - Wenwen Wang
AU  - Yan Li
AU  - Jun Yan Dai
AU  - Shixuan Wang
AU  - Jinjin Zhang
PY  - 2026
DA  - 2026/07/02
JO  - Nature Aging
DO  - 10.1038/s43587-026-01159-2
UR  - https://doi.org/10.1038/s43587-026-01159-2
AB  - 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.
SN  - 2662-8465
ER  -