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The present study is designed to investigate the effect of hydroxysafflor yellow A (HYA) on Staphylococcus aureus (S. aureus)-induced mouse endometrial inflammation and to explore its molecular mechanism. We established a mouse endometritis model by intrauterine injection of S. aureus and intrauterine injection of HYA for treatment. Immunohistochemistry, immunofluorescence, and Western blot were used to detect protein expression in uterine tissue, and qPCR was used to measure mRNA expression. HYA could significantly weak uterine pathologi