Kisspeptins inhibit ectopic endometrial cell invasion and angiogenesis by suppressing PI3K/AKT signaling pathway via CREB5 in endometriosis

Endometriosis (EMs) is a common gynecological disorder. According to the most widely recognized theory of retrograde menstruation, endometrial cells require completion of three key steps during ectopic implantation: adhesion, invasion, and angiogenesis. Although kisspeptin exerts anti-invasive and anti-angiogenic effects in multiple tumors, its potential inhibitory effects mediated through the KISS1 receptor (KISS1R) on EMs-related invasion and angiogenesis remain uncharacterized. This study aimed to identify regulatory genes in EMs pathogenesis via RNA sequencing and elucidate underlying molecular mechanisms. We performed a comparative transcriptomic analysis of ectopic endometrium (EC) and eutopic endometrium (EU) in 5 patients with EMs and control endometrium in 3 women without EMs. Then, we screened for genes that showed significant differences between EU and group, and even more pronounced differences between EC and EU, indicating a progressive change. Moreover, we identified the top 20 progressively altered genes during EMs development, including KISS1R. Furthermore, KEGG pathway analysis revealed that these progressively altered DEGs were mainly enriched in the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway. Previous studies suggest that the PI3K/AKT signaling pathway may mediate cell invasion and angiogenesis in EMs. Additionally, substantial evidence indicates that cAMP-response element binding protein (CREB5), a transcriptional regulator, can regulate the PI3K/AKT pathway. However, the mechanism of functional changes of CREB5 and PI3K/AKT in EMs is unclear. Our study validated the functional role of KISS1/KISS1R in EMs through animal experiments and cell experiments. It may suppress the cell invasion and angiogenesis of endometrial cells by reducing the phosphorylation levels of PI3K and AKT mediated by increasing CREB5. This mechanistic insight provides novel pathogenic explanations for EMs.