Context: Hepatic ischemia-reperfusion injury (HIRI) is a complex process observed during liver resection and transplantation. N-acetyl-l-tryptophan (l-NAT), an antagonist of neurokinin 1 receptor, has been used for the treatment of nausea and neurodegenerative diseases. Objective: This study investigates the protective effect of l-NAT against HIRI and explores the potential underlying mechanisms. Materials and methods: Adult male Sprague-Dawley (SD) rats were randomly divided into three groups: sham, I/R and I/R + l-NAT. HIRI model was generated by clamping the hepatic artery, portal vein and common bile duct with a microvascular bulldog clamp for 45 min, and then removing the clamp and allowing reperfusion for 6 h. BRL cells were exposed to 200 µM H₂O₂ with or without 10 µM l-NAT for 6 h. Results: After l-NAT intervention, the structure of hepatic lobules was intact, and no swelling was noted in the cells. Furthermore, cell viability was found to be significantly enhanced when compared with the controls (p < 0.05). The mRNA and protein expression levels of serine-threonine kinase 2 (RIP2) and interleukin-1β (IL-1β) were significantly increased in the I/R and H₂O₂ groups when compared with the controls; however, these levels were significantly decreased after l-NAT intervention. Similarly, IL-1β activity and caspase-1 activity were significantly decreased in the H₂O₂ group when compared with the controls, after l-NAT intervention. Conclusions: Our findings indicated that l-NAT may exert a hepatoprotective role in HIRI through inhibiting RIP2/caspase-1/IL-1β signaling pathway, which can provide evidence for l-NAT to be a potential effective drug against HIRI during clinical practice.

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