【Abstract】 Objective To investigate the effects of cultured Mycelium Cordyceps Sinensis (CMCS) on AMPK/SirT1 signaling pathway in carbon tetrachloride(CCl4)-induced liver fibrosis in mice. Methods Forty male C57BL/6 mice of SPF grade were randomly divided into normal control group, CMCS control group (3.0g/kg/d), Model control group, CMCS1.5g/kg group(1.5g/kg/d) and CMCS 3.0g/kg group (3.0g/kg/d). Mice were intraperitoneally injected with 10% CCl4 (2ml/kg) to induce liver fibrosis. 2 weeks later, serum levels of ALT, AST and TBil were measured. Inflammation and collagen deposition in liver tissue were observed by H&E and Sirius red stainings, respectively. The content of Hyp in liver tissue was detected by Jamall's hydrochloric acid hydrolysis method. The levels of IL-6, MCP-1, IFN-γ, TNF, IL-10 and IL-12p70 in liver tissue were detected by CBA analysis system. Immunohistochemistry was used to observe the expression of Collagen I and SirT1 in liver tissue. Real-time fluorescent quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) was used to observe the levels of Prkaa1, Prkaa2, Lkb1 and p53 in liver tissue. Results Compared with the normal control group, the serum levels of ALT, AST and TBil in the model control group were significantly increased(P<0.05). HE and Sirius red staining showed a large number of inflammatory cell infiltration and collagen deposition in the liver, respectively. The levels of Hyp content and the expressions of IL-6, MCP-1, and TNF in the liver tissues exhibited a significantly higher level (P<0.05). Conversely, the expressions of IL-10 and IL-12p70 displayed a decrease in significance (P<0.05). Immunohistochemical staining revealed an increase in the expression of Collagen I. And the staining of SirT1 was decreased in the hepatic sinusoidal space, while it was increased in the collagen deposition. RT-qPCR presented that the expression of Prkaa1, Prkaa2, and Lkb1 in liver tissue decreased, and the expression of p53 increased(P<0.05), respectively. CMCS could significantly reduce serum ALT and AST levels, decrease the expression of IL-6, MCP-1 and TNF in liver tissue(P<0.05), up-regulate the levels of IL-10 and IL-12p70(P<0.05), alleviate liver inflammation, collagen deposition and Hyp content, up-regulate the expression of SirT1 in the hepatic sinusoidal space, enhance the levels of Prkaa1, Prkaa2 and Lkb1(P<0.05), down-regulate collagen I and p53(P<0.05) in liver, respectively. In comparison with the CMCS 1.5g/kg group, the CMCS 3.0g/kg group exhibited a significant inhibitory effect on liver inflammation, collagen deposition and up-regulate AMPK/SirT1 expression(P<0.05). Conclusion CMCS could improve CCl4-induced liver fibrosis, and its mechanism was associated with the up-regulation of AMPK/SirT1 signaling pathway.