Bushen Zhuyun Recipe promotes histone H3K4me3 modification by regulating KLF4 to improve endometrial receptivity

The Bushen Zhuyun Recipe (BSZYR) is a traditional Chinese formula for treating infertility that can improve the pregnancy outcome via enhancing endometrial receptivity during in vitro fertilization and embryo transfer in the treatment of infertility patients. However, its molecular mechanism has not been completely explored. By establishing a mouse model of controlled ovarian hyperstimulation (COH), we evaluated the effects of BSZYR on the number of embryo implantation quantity and endometrial receptivity. By incubating endometrial epithelial cells (EECs) with BSZYR-medicated serum, adenovirus overexpressing/knockdown of KLF4, or transfected with si-MLL1, we studied the mechanism of BSZYR regulating histone H3K4me3 modification to promote endometrial marker factor HOXA10. We found that BSZYR improved endometrial receptivity and increased the number of embryos implanted in COH mice. And BSZYR induced KLF4 upregulation and facilitated its translocation into the nucleus in EECs. The increased KLF4 in the nucleus could interact with MLL1, recruiting it to the HOXA10 promoter and enhancing the enrichment of H3K4me3 in this region, which activated HOXA10 gene transcription, leading to endometrial receptivity improvement. These findings provide valuable pharmacological evidence supporting the clinical application of BSZYR in treating infertility from the perspective of epigenetics.