Objective,2,To explore the mechanism of Huazhi Rougan Granule （HZRG） in improving non-alcoholic steatohepatitis （NASH）-related fibrosis by network pharmacology methods.,Methods,2,Potential targets of HZRG for NASH were investigated through the analysis of network pharmacology. Male C57BL/6 mice were randomly divided into control group， model group and HZRG low dose group and HZRG high dose group， and 8 mice were allocated per group. The mice in each group were given a methionine choline-deficient diet （MCD） to induce NASH-related fibrosis model except those in the control group， and the corresponding pharmacological interventions were given at the same time of modeling for 4 consecutive weeks. HE staining was used to observe the pathological changes of liver tissues， and the non-alcoholic fatty liver disease activity score （NAS） was used in parallel； Sirius red staining and Masson’s trichrome staining were used to observe the liver collagen deposition； immunohistochemistry was used to detect the expressions of α-smooth muscle actin （α-SMA） and type I collagen α1 chain （Col1a1） in liver tissues， and the area of positive expression was analyzed by ImageJ. The reagent kit was used to detect TC and TG levels in liver tissues. Biochemical analyzer was used to measure the blood alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， lactate dehydrogenase （LDH） and alkaline phosphatase （ALP） levels of mice in each group， and ELISA kits was used to measure the level of serum tumor necrosis factor-α （TNF-α）. The expressions of fibrosis parameters α-SMA， Col1a1 and p53 were detected by western blot and immunofluorescence， respectively； and the expression of ,p53, mRNA was detected by RT-qPCR. LX2 cells were treated with different concentrations of TGF-β1 and/or Tenovin-6 for 24 hours， and related indicators were detected.,Results,2,①The results of network pharmacology suggested that p53 was a potential target for HZRG to exert its effect on. ②The results of HE， Sirius red and Masson’s trichrome staining showed hepatic lipid accumulation， inflammatory cell infiltration and fibrosis formation in mice of the model group， and the mice in the model group had larger area of positive expression of α-SMA and Col1a1 （,P,<,0.05） and higher NAS score （,P,<,0.05） than those in the control group. HZRG low and high dose groups of mice had reduced intra-hepatocellular lipid droplets and significantly reduced liver steatosis and inflammatory cell infiltration. The mice in the HZRG low and high dose groups had smaller area of positive expression of α-SMA and Col1a1 （,P,<,0.05） and lower NAS score （,P,<,0.05） than those in the model group. ③The serum levels of ALT， AST， LDH， ALP were higher in mice of the model group than those in mice of the control group （,P,<,0.05）. The serum levels of ALT， AST， LDH and TNF-α were lower in mice of the HZRG low and high dose groups than those in mice of the control group （,P,<,0.05）. The serum levels of ALP were lower in mice of the HZRG low dose groups than those in mice of the control group （,P,<,0.05）.④The TG and α-SMA protein expression in liver tissues of mice in the model group were higher than that in the control group （,P,<,0.05）. The α-SMA protein expression in liver tissues of mice in the HZRG high dose group was lower than that in the model group （,P,<,0.05）， and the TG and Col1a1 protein expression in liver tissues of mice in the HZRG low and high dose groups was lower than that in the model group （,P,<,0.05）. ⑤The difference in ,p53, mRNA expression in liver tissues of mice among each group was not statistically significant （,P,>,0.05）. ⑥The expression of p53 decreased in liver tissues of NASH mice and activated LX2 cells， and its expression could be up-regulated by HZRG and Tenovin-6； The elevated expression of p53 might alleviate the progression of liver fibrosis in NASH mice and inhibit LX2 cell activation.,Conclusion,2,The mechanism by which HZRG alleviates NASH-related fibrosis may be related to the upregulation of p53 expression.