2. Academic Validation
  3. Endometrial aging is accompanied by H3K27ac and PGR loss

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

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. yuyang5012@hotmail.com.
  • 6 National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. yuyang5012@hotmail.com.
  • 7 Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China. yuyang5012@hotmail.com.
  • 8 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. yuyang5012@hotmail.com.
  • 9 Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, Peking University, Beijing, China. yuyang5012@hotmail.com.
  • 10 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. hep2007@bjmu.edu.cn.
  • 11 National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. hep2007@bjmu.edu.cn.
  • 12 Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China. hep2007@bjmu.edu.cn.
  • 13 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. hep2007@bjmu.edu.cn.
  • 14 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. roseli001@sina.com.
  • 15 National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China. roseli001@sina.com.
  • 16 Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China. roseli001@sina.com.
  • 17 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. roseli001@sina.com.
  • # 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.

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