XBP1 promotes endometrial fibrosis through cGAS-STING signaling pathway in intrauterine adhesion

Intrauterine adhesion (IUA) was characterized by endometrial fibrosis, leading primarily to hypomenorrhea, infertility and recurrent miscarriage. Epithelial-mesenchymal transition (EMT) is now recognized as a key factor in the development of endometrial fibrosis. X-box binding protein 1 (XBP1), as a crucial transcription factor, has emerged as a potential target for anti-fibrosis treatment in the liver due to its role in various tissue fibrosis. However, the function and molecular mechanisms of XBP1 in the endometrium of patients with IUA are not well understood. In this study, we identified abnormal expression of XBP1, epithelial-mesenchymal transition (EMT) markers, and the cGAS-STING pathway in endometrial tissues from patients with IUA and in IUA-like mouse models. XBP1 was found to promote EMT in endometrial epithelial cells by activating the cGAS-STING pathway and cytoplasmic release of mitochondrial DNA. The addition of mitochondrial membrane inhibition VBIT-4 reversed TGF-β1-induced EMT in vitro. Inhibition of XBP1 reduced endometrial fibrosis and the cGAS-STING pathway activity in the IUA-like mouse models, while activation of XBP1 caused the opposite outcome. These findings indicate XBP1 may serve as a potential therapeutic target for IUA.