Luteolin attenuates Staphylococcus aureus -induced endometritis through inhibiting ferroptosis and inflammation via activating the Nrf2/GPX4 signaling pathway

ABSTRACT Endometritis, a local inflammatory disease, has been known as the most common cause of infertility in mares. In this study, we investigated the protective effects of luteolin on endometritis induced by Staphylococcus aureus ( S. aureus ) and further clarified the possible molecular mechanisms. An S. aureus –induced endometritis model was established by the infusion of S. aureus into the uterus. Luteolin was intraperitoneally administered to mice 1 h before S. aureus treatment. The results showed that the mice of the S. aureus group showed severe histological changes of uterine tissues, increased myeloperoxidase (MPO) activity, and elevated TNF-α, IL-1β, and IL-6 levels. These changes induced by S. aureus were dose-dependently inhibited by luteolin. Furthermore, luteolin inhibited MDA and Fe 2+ production and increased the production of GSH decreased by S. aureus . Luteolin prevented S. aureus –induced endometrial barrier disruption through up-regulating ZO-1 and occludin expression. Luteolin dramatically inhibited S. aureus –induced NF-κB activation. The expression of Nrf2 and HO-1 was increased by luteolin. In addition, the inhibitory effects of luteolin on S. aureus –induced endometritis were reversed in Nrf2 knockdown mice. In conclusion, these data indicated that luteolin protected mice against S. aureus –induced endometritis through inhibiting inflammation and ferroptosis via regulating the Nrf2 signaling pathway. IMPORTANCE Endometritis is an inflammatory disease of the endometrium, which is a common gynecological disease. Up to now, there is no evidence for the protective effects of luteolin on endometritis. The purpose of this study was to investigate whether luteolin has protective effects against S. aureus –induced endometritis and attempts to clarify the mechanism.