2. Academic Validation
  3. Melatonin affects trophoblast epithelial-to-mesenchymal transition and oxidative damage resistance by modulating GDF15 expression to promote embryo implantation

Melatonin affects trophoblast epithelial-to-mesenchymal transition and oxidative damage resistance by modulating GDF15 expression to promote embryo implantation

  • Commun Biol. 2025 Mar 8;8(1):396. doi: 10.1038/s42003-025-07834-1.
Guang Yang # 1 2 3,  Guidong Yao # 4 5 6 7,  Huihui Wang # 1 2 3,  Ran Jiang # 1 2 3,  Junnan Fang 1 2 3,  Jingyi Hu 1 2 3,  Yue Kong 1 2 3,  Haixia Jin 1 2 3,  Wenyan Song 1 2 3,  Zhaoting Wu 1 2 3,  Xianju Huang 1 2 3,  Yingpu Sun 8 9 10
Affiliations

Affiliations

  • 1 Center for Reproductive Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 2 Henan Key Laboratory of Reproduction and Genetics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 3 Henan Clinical Medical Research Center, Zhengzhou, China.
  • 4 Center for Reproductive Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. ygdzzu@163.com.
  • 5 Henan Key Laboratory of Reproduction and Genetics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. ygdzzu@163.com.
  • 6 Henan Clinical Medical Research Center, Zhengzhou, China. ygdzzu@163.com.
  • 7 NHC Key Laboratory of Birth Defects Prevention, Zhengzhou, China. ygdzzu@163.com.
  • 8 Center for Reproductive Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. syp2008@vip.sina.com.
  • 9 Henan Key Laboratory of Reproduction and Genetics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. syp2008@vip.sina.com.
  • 10 Henan Clinical Medical Research Center, Zhengzhou, China. syp2008@vip.sina.com.
  • # Contributed equally.
PMID: 40057595 DOI: 10.1038/s42003-025-07834-1
Abstract

Melatonin is widely observed in the female reproductive system and regulates trophoblast cell functions, but its effects on embryo implantation and underlying mechanisms are not well understood. By constructing an in vitro embryo culture model, we found that melatonin enhances migration and implantation in human and mouse trophoblast cells. It also significantly promoted HTR-8/SVneo cell proliferation, inhibited Apoptosis, enhanced migration, and mitigated oxidative damage. Further investigation revealed that melatonin promoted trophoblast cell migration and increased the in vitro implantation rate of HTR-8/SVneo spheroids by promotes epithelial-mesenchymal transition (EMT) via the Growth Differentiation Factor 15 (GDF15)-mothers against decapentaplegic homolog 2/3 (SMAD2/3) pathway. Additionally, melatonin increased the levels of Glutathione Peroxidase 4 (GPX4) and glutathione (GSH) in HTR-8/SVneo cells by upregulating the expression of GDF15, inhibiting Reactive Oxygen Species (ROS) accumulation, and increasing mitochondrial membrane potential, thus suppressing Apoptosis during oxidative stress. In conclusion, melatonin promotes EMT in trophoblast cells via GDF15-SMAD2/3 pathway and partially induces the expression of GPX4 through GDF15 to enhance oxidative damage resistance in trophoblast cells. These findings highlight melatonin's regulatory role in embryo implantation and suggest new avenues for exploring its biological effects in reproduction and clinical applications.

Figures
Products