Sinomenine protects mice against <i>Staphylococcus aureus</i> -induced endometritis through inhibition of P2X7 receptor-mediated ferroptosis and inflammation

ABSTRACT Endometritis is a major cause of infertility that adversely impacts both human reproductive health and livestock productivity. This study investigated the protective effects and underlying mechanisms of sinomenine (SIN) against Staphylococcus aureus ( S. aureus )-induced endometritis. Seventy-two adult female mice were randomly divided into six groups: control group, SIN group (100 mg/kg), S. aureus group (1 × 10 7 CFU per 200 μL PBS), and SIN (25 mg/kg, 50 mg/kg, and 100 mg/kg, respectively) + S. aureus groups. Uterine tissues were collected for analysis. Inflammatory factors, ferroptosis, and P2X7 signaling pathway-associated proteins were detected. S. aureus infection induced severe uterine pathology, significantly elevating myeloperoxidase (MPO) activity and pro-inflammatory cytokine levels (TNF-α, IL-1β, and IL-6; P &lt; 0.05). Infection also triggered ferroptosis and upregulated P2X7 pathway components ( P &lt; 0.05). SIN administration dose-dependently attenuated these pathological changes, reversing endometritis severity ( P &lt; 0.05). These findings demonstrate that SIN alleviates S. aureus -induced endometritis by suppressing P2X7 receptor-mediated ferroptosis, providing a mechanistic rationale for its therapeutic potential. IMPORTANCE We demonstrated for the first time that SIN could protect mice against S. aureus -induced endometritis. The mechanism was through inhibition of P2X7 receptor-mediated ferroptosis, which provides a theoretical basis for SIN treatment of endometritis.