Rictor stability mediated by USP9X regulates embryo implantation by participating in lipid metabolism of endometrium

The receptive endometrium is a prerequisite for successful embryo implantation, and abnormal endometrial receptivity would lead to infertility. Many key proteins involved in endometrial receptivity have been confirmed to undergo post transcriptional modifications. However, there are limited reports on deubiquitination modification during this process. Our previous studies found that Rictor participated in the endometrial receptivity, and maintained at a high level in the endometrium during implantation, but the mechanism for maintaining stability of Rictor protein remains unclear. Here, we showed that USP9X expression in endometrium was dynamic with the establishment of endometrial receptivity, and promoted the protein stability of Rictor through deubiquitination. Inhibition of USP9X could suppress the adhesion action of trophoblast cells to endometrial epithelial cells, reduce the filamentous pseudopodia of epithelial cells, and inhibit the epithelial mesenchymal transformation. Rictor is partially responsible for the derailment of epithelial cell transformation in response to USP9X inhibition. Membrane fluidity mediated by lipid metabolism is involved in regulation of Rictor on endometrial receptivity. This study revealed the role of USP9X in endometrial receptivity for the first time, and confirmed that Rictor was the target protein of USP9X in endometrium. In addition, we described the unique lipidomics characteristics of the endometrial epithelial cells regulated by Rictor. These data would further improve the molecular network of endometrial receptivity, supplement the regulatory factors of lipid metabolism in endometrial cells, and provide insights into the new therapeutics, pre-diagnosis, and preventive strategies for the derailment of endometrial receptivity and subsequently adverse "ripple effect" including infertility.