〔Abstract〕 Objective To investing ate the milk-derived hexapeptide PGPIPN and its truncated pentapeptide PGPIP to alleviate chronic alcoholic liver injury in mice and its associated molecular mechanisms. Methods Sixty Kunming mice were randomly divided into control group, model group, GSH group, PGPIPN group, and truncated pentapeptide PGPIP group. The model of chronic alcoholic liver injury in mice was established by gavage with gradient alcohol. Drug intervention was given at the same time for 12 weeks. Liver HE staining was used to analyze the pathological effects of each treatment group on alcoholic liver injury in mice. Primary mouse hepatocytes and human normal hepatocyte line L-02 were isolated and culturedin vitro. The appropriate PGPIPN induction concentrations of both cells were determined by WST-1 method. L-02 cells were induced at different times. The expression of FoxO3 a and phosphorylated FoxO3 a protein were detected by Western blot to determine the appropriate induction time. The subcellular localization of FoxO3 a in L-02 cells was detected by cellular immunofluorescence. The mRNA changes of FoxO3 a and MnSOD genes in primary hepatocytes and L-02 cells of mice in different treatment groups were detected by qRT-PCR. Results The pathological examination of PGPIPN group and PGPIP group was similar to that of GSH group, and the liver injury of mice was significantly reduced. Medium and high concentrations of PGPIPN were respectively selected to induce mouse primary hepatocytes and L-02 cells. At 16 hours, the expression of FoxO3 a protein in L-02 cells increased significantly. FoxO3 a protein was mainly expressed in the nucleus. In addition, mRNA levels in both types of cells increased significantly after induction with the corresponding dose of PGPIPN. Conclusion PGPIPN and truncated pentapeptide PGPIP can reduce chronic alcoholic liver injury in mice. The mechanism may be to reduce alcohol-induced oxidative stress through FoxO3 a-MnSOD signaling pathway.