Exploring the Early Endometrial–Blastocyst Interactome in Endometriosis: An Integrative Study

<b>Background:</b> Background: Endometriosis affects 10% of women of reproductive age. Despite the well-known association between endometriosis and infertility, the mechanisms underlying this association remain to be elucidated. <b>Methods:</b> Implantation and pregnancy success rates were evaluated by a retrospective study of patients that underwent IVF using euploid embryos comparing healthy vs. endometriosis patients. To study the early embryo-endometrial dialogue, an interactome network was constructed using public RNAseq data from normal secretory-phase endometrial samples and day-5 blastocyst. Public bulk and single-cell RNAseq data from endometrial samples of endometriosis patients were used to detect alterations in the interactome. <b>Results:</b> Endometriosis patients required significantly more IVF attempts compared to those without endometrial pathologies; however, once pregnancy was achieved, the evolution of both groups was similar. The interactome network between normal endometrium and day-5 blastocyst showed a significant enrichment of pathways associated with tissue remodelling, angiogenesis, and immune regulation, which were altered in endometriosis patients. Endometriosis patients also presented an increased frequency and activation of NK, CD4⁺, and CD8⁺ cells, which interfere with embryo-endometrial dialogue. <b>Conclusions:</b> We identified key molecular processes affected by endometriosis specifically involved in the early interaction between the blastocyst, decidual, and resident immune cells, that may underline the reported fertility problems associated with endometriosis.