Altered IRE1α-Dependent Decidual Programming Links Impaired Inflammation and Angiogenesis in Recurrent Implantation Failure

Background: Decidualization alters the endometrial stromal cells (EnSC) secretome, allowing sterile inflammation associated with embryo implantation, but mechanisms that lead to alterations in this process are still unknown. We evaluated whether impaired IRE1α-mediated endoplasmic reticulum (ER) stress signalling contributes to defective angiogenic decidual programming in patients with recurrent implantation failure (RIF). Methods: Candidate pathways were identified with bioinformatic analyses of endometrial arrays and validated in endometrial biopsies from fertile and RIF women (secretory phase) by RT-qPCR and in isolated EnSC by flow cytometry. Functional alterations were evaluated using trophoblast spheroid and endothelial cell migration assays. ER stress was pharmacologically induced in EnSC using thapsigargin. Results: RIF endometria displayed impaired in vivo decidualization, with reduced expression of IGFBP1 and PGR, together with altered expression of molecules involved in blastocyst adhesion. Conditioned media from RIF-derived EnSC-impaired trophoblast outgrowth. RIF samples displayed an anti-angiogenic and altered inflammatory profile, characterized by reduced intracellular IL-1β accumulation, decreased VEGFA, and increased sFlt1 expression. Bioinformatic analyses identified IRE1α pathway as a central altered network associated with angiogenesis. Consistently, RIF samples showed reduced expression of IRE1α, sXBP1, and NLRP3. Moreover, ER stress induction in EnSC promoted endothelial cell migration. Conclusions: RIF is associated with defective angiogenic decidual programming linked to impaired IRE1α-mediated ER stress signalling. These findings identify the IRE1α axis as a potential pathway of interest for future therapeutic exploration in recurrent implantation failure.