AbstractThis study was to examine the protective effects of curcumin/cyclodextrin polymer inclusion complex (CUR/CDP) on ethanol‐induced liver injury in mice and to explore its potential mechanisms. In the ethanol‐induced acute injury mouse model, the effects of pretreatment with silymarin, cyclodextrin polymer (CDP), curcumin (CUR) and CUR/CDP at low, middle, and high doses were evaluated by biochemical and histopathological examination. The liver index, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels in serum of the mice were measured. The superoxide dismutase (SOD), glutathione peroxidase (GSH‐PX) activities, and malondialdehyde (MDA) level in liver tissue were assessed by assay kits. Moreover, hematoxylin–eosin (HE) staining was carried out to observe pathological changes of liver. Western blotting was performed for determining the changes in the expressions of DNA damage‐associated proteins. The results showed that compared with the control group, the liver index and the levels of ALT, AST, LDH, and MDA in the ethanol treatment group were significantly increased and the activities of GSH‐Px and SOD were obviously decreased. However, pretreatment with silymarin, CUR, and CUR/CDP reversed the change of above indicators except CDP. Moreover, CUR/CDP at high dose further weakened the liver index, inhibited the biochemical indexes, and enhanced the activities of antioxidant enzymes to a greater extent than silymarin and CUR. Western blot analysis indicated that CUR/CDP significantly down‐regulated the expressions of DNA damage‐related proteins including p‐ATM, γ‐H2AX, p‐p53, and p‐p38MAPK, which inhibited ethanol‐induced the G2/M arrest and ultimately prevented liver function from oxidative stress injury. These results indicated that CUR/CDP possessed good protective effect on mice liver damage in vivo by increasing the activities of GSH‐Px and SOD to suppress DNA damage.