Farnesoid X receptor protects against lipopolysaccharide-induced endometritis by inhibiting ferroptosis and inflammatory response

Endometritis is an inflammatory condition that affects the endometrium; it is induced by bacterial infection and often leads to infertility and repeated abortions. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that mediates a variety of inflammatory diseases. In the present study, we determined the protective effects of FXR on lipopolysaccharide (LPS)-induced endometritis in mice and the underlying mechanisms. The results showed that LPS administration reduced the expression of FXR in the uterus, and treatment with the FXR agonist GW4064 and fexaramine significantly alleviated the endometritis induced by LPS. In addition, compared with wild-type (WT) mice, FXR-knockout mice had more severe inflammatory responses in their uteri after LPS treatment. Moreover, ferroptosis was increased during LPS-induced endometritis, as shown by increased levels of malondialdehyde (MDA) and iron, and decreased levels of superoxide dismutase (SOD), glutathione (GSH), GXP4 and SLC7A11. In addition, inhibition of ferroptosis by treatment with ferrostation-1 (Fer-1) and liproxstatin (Lip -1) alleviated LPS-induced endometritis. Additionally, FXR-knockout mice were used to determine the relation-ship between FXR and ferroptosis. The results showed that knockout of FXR induced ferroptosis, and an FXR agonist inhibited LPS-induced ferroptosis. Finally, the regulatory effects of obeticholic acid (OCA) on FXR/fer-roptosis and endometritis were assessed. The results showed that treatment with OCA increased the expression of FXR, decreased the levels of ferroptosis, and inhibited the endometritis induced by LPS. In conclusion, the results showed that activation of FXR can alleviate LPS-induced endometritis by inhibiting ferroptosis, and FXR may be a potential therapeutic target for treating endometritis.

Automated summary

This study investigated the protective effects of FXR on LPS-induced endometritis and the underlying mechanisms. The results showed that FXR agonists alleviated endometritis, while FXR knockout mice had more severe inflammatory responses. Ferroptosis was increased during endometritis, and its inhibition alleviated the condition. Activation of FXR by OCA decreased ferroptosis and inhibited endometritis.