Activation of AMPK/SIRT1/PGC-1α Signaling Pathway by Casticin Protects Against S. aureus-Induced Endometritis

Endometritis is a prevalent reproductive disorder predominantly triggered by microbial infection. Casticin exhibits diverse pharmacological properties, including anti-inflammatory and anti-tumor activities. However, its protective potential against endometritis remains poorly documented. Thus, this study aimed to investigate the protective efficacy and underlying mechanism of casticin in S. aureus-induced endometritis. ELISA was used to quantify the levels of TNF-α and IL-1β, while ferroptosis-related indicators were measured using commercial assay kits and Western blot analysis. The results showed that casticin significantly alleviated S. aureus-induced myeloperoxidase (MPO) activity, TNF-α and IL-1β production, and nuclear factor-kappa B (NF-κB) activation. Additionally, casticin diminished the ferroptosis-associated elevation of malondialdehyde (MDA) levels and intracellular iron content, while concurrently enhancing glutathione (GSH) biosynthesis and upregulating the expression of GPX4 and xCT. Furthermore, the expression of sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were increased by casticin. In vitro, the inhibition of casticin on S. aureus-induced inflammation and ferroptosis were prevented by AMPK inhibitor compound C or SIRT1 inhibitor EX-527. In conclusion, our findings indicate that casticin mitigates S. aureus-induced endometritis by suppressing inflammation and ferroptosis, a mechanism mediated through the regulation of the AMPK/SIRT1/PGC-1α signaling pathway.