BACKGROUND: Intrauterine adhesions (IUA) seriously affect female reproductive function, but the clinical treatment effect is not good. Semaglutide and Dulaglutide, receptor agonists of the gastrointestinal hormone GLP-1, have been reported to alleviate IUA. We sought to determine whether liraglutide, also a GLP-1 receptor agonist, would exert a protective effect and explore the underlying mechanism.
METHODS: The IUA rat models were conducted via the mechanical damage method and rats were administrated with liraglutide. The inflammation and collagen fibrosis were evaluated via hematoxylin-eosin and Masson staining. The content of E-cadherin and N-cadherin was measured by immunohistochemistry, immunofluorescence, and Western blot. To stimulate IUA, human endometrial organoids were treated with RU486, and primary human endometrial epithelial cells were treated with TGF-β. SuperPred analysis was to predict the potential targets of liraglutide, with cellular thermal shift assay to detect its interaction with NF-κb.
RESULTS: Liraglutide treatment reduced endometrial inflammation, collagen fibrosis, and EMT in IUA rats as well as human organoid IUA models. NF-κb phosphorylation was up-regulated in the IUA model group and was reversed by liraglutide treatment. Database predictions suggested that NF-κb may be a predicted direct target of liraglutide and our results confirmed that. Further results showed that in human endometrial organoids, interfering with the targeting of NF-κB by liraglutide attenuated the effects of liraglutide on inflammation, fibrosis, and EMT in the IUA models.
CONCLUSIONS: Liraglutide reduces EMT by directly targeting NF-κb and inhibiting NF-κb phosphorylation, thereby improving IUA.