PIEZO1 governs endometrial function via Ca2+/NFATc2 transcriptional network

Recurrent implantation failure (RIF) remains a significant challenge in assisted reproductive technology, yet its underlying pathogenesis is poorly understood. Successful embryo implantation requires synchronization between the blastocyst and a receptive uterus. Mechanosensitive ion channel PIEZO1 has emerged as a key regulator in various physiological and pathological contexts. However, the role of PIEZO1 in embryo implantation remains unclear. This study aims to elucidate the role and molecular mechanism of PIEZO1 in embryo implantation and to explore its clinical relevance in patients with RIF. The expression levels of PIEZO1 in endometrial tissues from patients with RIF and healthy controls were analyzed by immunohistochemistry. A uterine-specific Piezo1 knockout mouse model was established to assess the role of PIEZO1 during embryo implantation. Ca 2+ imaging was employed to determine PIEZO1 mediated Ca 2+ influx in endometrial cells. Mechanical stretch was applied to study PIEZO1 regulated signaling pathway. mRNA sequencing of mice endometrium was applied to examine differential regulated pathways. Chromatin immunoprecipitation sequencing (ChIP-seq), ChIP-qPCR and co-immunoprecipitation (Co-IP) were employed to identify NFATc2 target genes and transcriptional partners downstream of PIEZO1. The effect of Nfatc2 silencing on embryo implantation was evaluated. PIEZO1 expression was significantly up-regulated in the human endometrium during the secretory phase compared to the proliferative phase. However, its expression was markedly reduced in patients with RIF in the secretory phase. Uterine conditional deletion of Piezo1 in mice resulted in subfertility due to impaired endometrial receptivity and implantation failure. Mechanistically, PIEZO1 deficiency reduced both Yoda1 and mechanical stretch-induced Ca 2+ influx and NFATc2 activation. Consistent with this, in vivo knockdown or blockade of NFATc2 activation inhibited embryo implantation in mice. Further study revealed that NFATc2 regulates a subset of PGR target genes by forming a transcriptional complex with PGR. These findings highlight the critical role of PIEZO1 in uterine receptivity during embryo implantation through the Ca 2+ /NFATc2 axis. Defects in this pathway represent a potential mechanism underlying implantation failure, suggesting PIEZO1 as a promising therapeutic target for implantation failure.