To observe the protective effect of wall-broken Ganoderma lucidum spore powder(GLS) on hepatocellular carcinoma in mice and explore its mechanism of action.Methods:Ten young mice were assigned to the control group.Forty young mice were used to construct a hepatocellular carcinoma model using diethylnitrosamine(DEN) and carbon tetrachloride(CCl4).The mice were numbered and randomly divided into the model group and GLS low，medium，and high-dose groups(10 mice per group) according to computer-generated random numbers.From week 8，the GLS low，medium，and high-dose groups were administered 0.25，0.5，and 1.0 g/kg GLS by gavage，respectively.The control group was given an equal amount of saline.Treatment continued once daily until week 22.At the end of the experiment，body weight，liver weight，and liver index were measured.Serum levels of GOT and GPT were assessed by colorimetry，and immunohistochemistry was used to detect the expression of Ki67 in liver tissue.Liver appearance and histopathological changes were observed by hematoxylin-eosin(HE) staining.ELISA was used to measure serum levels of IL-1β，IL-6，and TNF-α.The hydroxylamine method and TBA method were used to detect SOD and MDA levels in liver tissue，respectively.Western blot was used to examine the expression of Nrf2 and Keap1 proteins.Results:Compared to the control group，the model group showed decreased body weight and body gain(P<0.01)，and increased liver weight and liver index(P<0.01，P<0.05).Compared to the model group，the GLS medium and high-dose groups showed significantly increased body weight and body gain(P<0.01)，while the low-dose group showed no significant difference(P>0.05).The liver weight and liver index showed no significant differences between GLS groups and the model group(P>0.05).Serum levels of GOT and GPT were significantly higher in the model group than in the control group(P<0.01)，but these levels were lower in the GLS groups than in the model group(P<0.05，P<0.01).No significant differences were found between the GLS groups in terms of the serum levels of GOT and GPT(P>0.05).The Ki67-positive expression rate in liver tissue was significantly higher in the model group than in the control group(P<0.01)，but lower in the GLS groups than in the model group(P<0.05)，with no significant differences among the GLS groups(P>0.05).Gross observation showed fewer cancer nodules in the GLS groups compared to the model group.HE staining revealed that liver lobule structure disorder and hepatocyte degeneration were significantly alleviated in the GLS groups compared to the model group，with hepatocellular carcinoma cells arranged in a more orderly fashion.Serum levels of IL-1β，TNF-α，and IL-6 were higher in the model group than in the control group(P<0.01)，but these levels were lower in the GLS groups than in the model group(P<0.05，P<0.01)，with no significant differences among the GLS groups(P>0.05).Liver tissue SOD levels were lower(P<0.01) and MDA levels were higher(P<0.01) in the model group compared to the control group，but GLS treatment increased SOD levels(P<0.05，P<0.01) and decreased MDA levels(P<0.05) in the GLS groups.No significant differences in SOD and MDA levels were observed among the GLS groups(P>0.05).Nrf2 protein expression was lower(P<0.05) and Keap1 protein expression was higher(P<0.01) in the model group compared to the control group.In the GLS medium and high-dose groups，Nrf2 protein expression was higher(P<0.05)，and Keap1 protein expression was lower(P<0.05，P<0.01) compared to the model group.No significant differences in Nrf2 and Keap1 protein expression were observed among the GLS groups(P>0.05).Conclusion:GLS significantly improves hepatocellular carcinoma in DEN/CCl4-induced mice.The mechanism may be related to the activation of the Nrf2/Keap1 signaling pathway，which suppresses inflammatory response and oxidative stress damage.