Liraglutide ameliorates intrauterine adhesion by inhibiting NF-κb phosphorylation and reducing epithelial-mesenchymal transition

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.