Objective: To evaluate the therapeutic potential of thymoquinone in rats with sepsis and explore the underlying molecular mechanism. Methods: Cecum ligation and puncture (CLP) was used to induce sepsis rats model. Thymoquinone (20 mg/kg) was intraperitoneally injected every 12 h for three days after CLP

with or without intraperitoneal injection of the sirtuin1 (SIRT1) inhibitor EX527 (5mg/kg). The expression of fasting blood glucose and fasting insulin were detected after the designed treatment. The relative expression of aspartate aminotransferase (AST) and lactic alanine transaminase (ALT) in serum were determined by Reit’s analysis method. Levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in liver tissues were analyzed by immunohistochemistry. Levels of p-Akt

t-Akt

SIRT1

p-signal transducer and activator of transcription 3 (STAT3)

PEPCK

G6Pase and t-STAT3 were evaluated by Western blot. The expression of reactive oxygen species (ROS) in liver tissues was detected by DCFH-DA fluorescence probe and the level of acetylated STAT3 in liver tissues was determined by immunoprecipitation analysis. Results: The hepatic SIRT1/STAT3 pathway of septic rats was significantly inhibited

expressions of AST

ALT

IL-6 and TNF-α were up-regulated

and levels of fasting blood glucose and fasting insulin were increased. Thymoquinone administration was able to promote STAT3 phosphorylation and alleviate liver dysfunction and glucose metabolism disorder. EX527 significantly diminished the protective effect of thymoquinone on sepsis induced liver injury

hyperglycaemia and STAT3 inactivation. Conclusion: Thymoquinone is a potential therapeutic agent for sepsis-associated liver injury and glucose metabolism disorder and its mechanism may be realized by activating SIRT1/STAT3 pathway.