Objective:To investigate the role of hydrogen-rich salt water in improving depression-like symptoms and its possible molecular mechanism in rats.Methods:The experiment was divided into two stages. In the first stage, 35 healthy male SD rats were randomly divided into control group, model group, high-dose group, medium-dose group, and low-dose group ( n=7); rats in the control group and model group were gavaged with 8 mL/kg normal saline per d, and rats in the high-dose group, medium-dose group, and low-dose group were fed with 8 mL/kg hydrogen-rich saline water (containing 2, 1, and 0.5 ppm hydrogen) per d; except for the control group, the other groups were depressed with chronic unpredictable mild stimulation (CUMS) for 4 weeks. In the second stage, 30 healthy male SD rats were randomly divided into hydrogen water group, hydrogen water+fluoxetine group, and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibition group ( n=10); optimal hydrogen concentration (0.8 ppm) hydrogen-rich saline water (8 mL/kg) per d was given to rats of these 3 groups by gavage; fluoxetine (5 mg/kg) by gavage was given to the hydrogen-water+fluoxetine group, and all-transretinoic acid (10 mg/kg) by gavage was given to the Nrf2 inhibition group; CUMS was given for 4 weeks in these 3 groups. Rats were weighed at fixed times at each weekend. Four weeks after intervention, the total distance and average speed of rats in each group were determined by open field test. After open field test, blood was collected from the orbital veins from all rats; serum superoxidase dismutase (SOD) and malondialdehyde (MDA) contents were determined by ELISA. The expressions of brain-derived neurotrophic factor (BDNF), heme oxygenase-1 (HO-1), Nrf2, and phosphorylated Nrf2 (p-Nrf2) in the hippocampal CA3 region were detected by Western blotting. Results:(1) In the first stage, after 3 and 4 weeks of intervention, as compared with the model group, the body weight of the rats in the high-dose group, medium-dose group, and low-dose group increased significantly ( P<0.05). As compared with the model group, the medium-dose group, and low-dose group had significantly increased total distance and average speed, significantly increased serum SOD content, significantly decreased serum MDA content, significantly increased BDNF and HO-1 expressions and decreased p-Nrf2 expression in the CA3 region of the hippocampus ( P<0.05). (2) In the second stage, after 3 and 4 weeks of intervention, as compared with the Nrf2 inhibition group, the body weight of the hydrogen water group and hydrogen water+fluoxetine group increased significantly ( P<0.05). As compared with the Nrf2 inhibition group, the hydrogen water group and hydrogen water+fluoxetine group had significantly increased total distance and average speed, significantly increased serum SOD content, significantly decreased serum MDA content, statistically increased BNDF and HO-1 expressions in the CA3 region of the hippocampus, and the hydrogen water+fluoxetine group had significantly increased Nrf2 and p-Nrf2 expressions in the CA3 region of the hippocampus ( P<0.05). As compared with the hydrogen water group, the hydrogen water+fluoxetine group had significantly increased BNDF and HO-1 expressions and increased p-Nrf2 expression in the CA3 region of the hippocampus ( P<0.05). Conclusion:Hydrogen-rich salt water can increase the serum SOD and reduce the serum MDA, increase the BDNF and HO-1 protein expressions in the hippocampal areas of depressed rats, thereby improving the depression-like symptoms; the synergistic effect of hydrogen-rich saline water and fluoxetine on anti-depression may be related to antioxidant effect of Nrf2 signaling.