Inhibiting Endoplasmic Reticulum/Plasma Membrane contact ameliorates endometrial fibrosis by preventing senescence in endometrial epithelial cells.

Abstract

Intrauterine adhesion (IUA) is characterized by the formation of endometrial fibrosis within the uterine cavity, which can lead to thin endometrium, hypomenorrhea, infertility, and recurrent abortion, exerting a detrimental impact on women's physical and psychological health. Currently, its pathogenesis is not fully elucidated, absence of effective therapies and coupled with a high recurrence rate. In this study, single-cell RNA sequencing was applied for the first time to a mouse IUA model, revealing significant changes in the expression of senescence markers in endometrial epithelial cells (EECs). Specifically, upregulation of Cdkn1a, and Il6, and downregulation of Lamin B1. Further bioinformatic analysis showed significant enrichment of gene sets related to calcium overload, ER stress, and Endoplasmic Reticulum/Plasma Membrane (ER/PM) contacts in the EECs of IUA mice. Mechanistically, ER/PM contacts in IUA activates the STIM1/Orai1 channel complex, leading to ER stress and intracellular calcium overload, which induces cellular senescence in EECs and ultimately drives IUA progression. Intrauterine administration of the STIM1/Orai1 channel inhibitor BTP2 significantly suppressed ER/PM contacts-induced senescence in EECs and effectively alleviated endometrial fibrosis in the mouse IUA model. In conclusion, targeting the STIM1/Orai1 calcium channel dependent on ER/PM contact sites significantly ameliorates endometrial fibrosis, offering a promising therapeutic strategy for IUA.