Pyruvate kinase M2 -mediated histone lactylation alters three-dimensional genomic architecture in polycystic ovary syndrome

  • Signal Transduct Target Ther. 2025 Nov 19;10(1):376. doi: 10.1038/s41392-025-02468-5.
Chuanjin Yu  #  1  2  3 ,  Tingting Liu  #  4 ,  Yishu Wang  #  1  2  3  5 ,  Xinghui Guo  #  4 ,  Yujie Chen  6 ,  Yifan Zhao  5 ,  Xia Liu  5 ,  Weiwei Huang  1  2  3 ,  Shuoyang Zhao  1 ,  Jiaying Mo  7 ,  Hongtao Hu  8 ,  Pingping Lv  9 ,  Xiaotao Wang  1  2  3 ,  Zuwei Yang  1  2 ,  Jiexue Pan  1  2  3 ,  Guolian Ding  1  2  3 ,  Jianzhong Sheng  9 ,  Xinmei Liu  10  11  12 ,  Hongbo Yang  13  14  15 ,  He-Feng Huang  16  17  18  19  20
Affiliations
  • 1. Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
  • 2. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
  • 3. Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
  • 4. Zhongda Hospital, Advanced Institute for Life and Health, School of Public Health, Southeast University, Nanjing, China.
  • 5. The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 6. Morphology and spatial multi-omics core facility Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, Chin, China.
  • 7. Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 8. Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 9. Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 10. Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. [email protected].
  • 11. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. [email protected].
  • 12. Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China. [email protected].
  • 13. Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. [email protected].
  • 14. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. [email protected].
  • 15. Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China. [email protected].
  • 16. Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. [email protected].
  • 17. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. [email protected].
  • 18. Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China. [email protected].
  • 19. The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • 20. Key Laboratory of Reproductive Genetics (Ministry of Education), Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41253762 DOI: 10.1038/s41392-025-02468-5
Abstract

Polycystic ovary syndrome (PCOS) is a frequent endocrine and metabolic imbalance that typically occurs in women of reproductive age. Its molecular pathophysiology is yet unknown, especially the ovarian cellular metabolic inefficiency that causes the transcriptional dysregulation of key genes linked to PCOS. Here, we discovered that one transcriptional-like regulator that causes PCOS is nuclear Pyruvate Kinase M2 (nPKM2). Using multiomics techniques, we show that enhanced lactylation of histone 3 on lysine residues 9 and 18 is linked to nPKM2 binding to the genome, changing the three-dimensional architecture of the genome. Genomic compartment switching, topologically associated domain fusion, and novel enhancer-promoter interactions subsequently enhance the expression of PCOS-related genes, including CYP17A1 and CYP11A1. In mice, ectopic expression of Pkm2 in female GCs consistently presented PCOS-like traits, such as interrupted estrous cycles, hyperandrogenism, and so on. Importantly, whole-organ tracing imaging directly unfolded the number of small follicles, which increased highly in Pkm2-tdtomato transgene mice compared with control. Furthermore, pharmacological inhibition of the nuclear accumulation of PKM2 mitigated PCOS-like symptoms in mice and restored a wild-type-like transcriptome. This study demonstrates the important function of PKM2-mediated histone lactylation in regulating the three-dimensional chromatin architecture and highlights PKM2 as a potential therapeutic target for PCOS treatment.