Objective To explore whether voluntary wheel running affects liver oxidative stress by regulating the Nrf2 / HO-1 pathway, thereby alleviating HFFC diet-related lipid deposition in the liver. Methods Eight-week-old C57BL/ 6J mice were randomly divided into a normal diet group ( NC group, n= 10) and high-fat, fructose, and cholesterol diet group (HFFC group, n= 20) after 1 week of adaptive feeding. Ten weeks of feeding later, mice in the HFFC group were divided into a quiet group (HFFC group, n= 10) and HFFC combined with exercise group (HFFC+EX group, n= 10). HFFC + EX group mice were caged with voluntary running wheels for free movement, and the number of running wheels was recorded every day for 8 weeks. After the last treatment, the mice were sacrificed by fasting for 12 hours at an interval of 24 hours, and the blood and liver were collected for analysis. Results ( 1) Body weight, liver weight, and liver index of mice fed the HFFC diet were significantly higher than those of the NC group, which significantly decreased after exercise (P<0. 05). ( 2) Compared with the NC group, HDL-C and LDL-C in the HFFC group were significantly increased, and the LDL-C level was significantly decreased after 8 weeks of exercise (P<0. 05). (3) The liver fat droplet area and liver TG content in the HFFC group were significantly higher than those in the NC group, whereas those in HFFC + EX group were significantly decreased (P<0. 05). (4) Compared with the NC group, the content of oxidase MDA in the HFFC group were significantly increased, and nuclear translocation and gene expression of Nrf2 were significantly decreased. After exercise, the activities of SOD and T-AOC were significantly increased, and the nuclear translocation and gene expression of Nrf2 and expression levels of HO-1 and SOD-1 were significantly increased ( P<0. 05). (5)The number of apoptotic hepatocytes and CHOP expression in the HFFC diet group were significantly higher than those in the NC group, whereas the number of apoptotic hepatocytes, and CHOP and Bax / Bcl-2 expression in the exercise group were significantly lower than those in the NC group ( P<0. 05). Conclusions Voluntary wheel can alleviate HFFC diet induced liver lipid deposition by regulating the Nrf2 / HO-1 pathway, thereby alleviating oxidative stress and reducing apoptosis in liver cells.