Endometrial aging is accompanied by H3K27ac and PGR loss

  • Nat Aging. 2025 May;5(5):816-830. doi: 10.1038/s43587-025-00859-5.
Yue Wang  #  1  2  3  4 ,  Ping Zhou  #  1  2  3  4 ,  Hongying Shan  #  1  2  3  4 ,  Xiyao Liu  #  1  2  3  4 ,  Ming Cheng  1  2  3  4 ,  Zhenhong Ye  1  2  3  4 ,  Xiunan Chen  1  2  3  4 ,  Baoying Liao  1  2  3  4 ,  Tianliu Peng  1  2  3  4 ,  Chenxi Xiao  1  2  3  4 ,  Ziying Huang  1  2  3  4 ,  Yunshu Dong  1  2  3  4 ,  Yang Yu  5  6  7  8  9 ,  Heng Pan  10  11  12  13 ,  Rong Li  14  15  16  17
Affiliations
  • 1. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
  • 2. National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
  • 3. Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China.
  • 4. Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China.
  • 5. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. [email protected].
  • 6. National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. [email protected].
  • 7. Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China. [email protected].
  • 8. Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. [email protected].
  • 9. Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, Peking University, Beijing, China. [email protected].
  • 10. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. [email protected].
  • 11. National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. [email protected].
  • 12. Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China. [email protected].
  • 13. Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. [email protected].
  • 14. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. [email protected].
  • 15. National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. [email protected].
  • 16. Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China. [email protected].
  • 17. Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 40394215 DOI: 10.1038/s43587-025-00859-5
Abstract

Whether and how endometrial aging affects fertility remains unclear. In our in-house clinical cohort at the Center for Reproductive Medicine of Peking University Third Hospital (n = 1,149), we observed adverse pregnancy outcomes in the middle-aged group after excluding aneuploid embryos, implying the negative impact of endometrial aging on fertility. To understand endometrial aging, we performed comprehensive transcriptomic profiling of the mid-secretory endometrium of young (<35 years) and middle-aged (≥35 years) patients. This analysis revealed that H3K27ac loss is linked to impaired endometrial receptivity in the middle-aged group. We eliminated H3K27ac in young human endometrial stromal cells and observed reduced Progesterone Receptor (PGR), a critical regulator of endometrial receptivity. Lastly, we validated the association between H3K27ac/PGR loss and uterine aging in a mouse model. Our findings establish H3K27ac as a critical regulator of PGR and demonstrate that endometrial H3K27ac loss is associated with aging-related fertility decline. This work provides valuable insights into enhancing the safety and efficacy of assisted reproductive technologies in future clinical practices.

Products