Objective:The protective effect and mechanism of seabuckthorn polysaccharides on insulin-resistant HepG2 cells against oxidative stress was investigated.Methods:The seabuckthorn polysaccharide was extracted by water extraction and alcohol precipitation method, and the polysaccharide content was determined by the phenol sulfuric acid method. The CCK-8 method was used to determine the effects of different concentrations of sea-buckthorn polysaccharides on the viability of HepG2 cells. HepG2 cells were induced with a medium containing 5×10-8 mol/L insulin for 24 hours to establish a HepG2 cell insulin resistance model. A kit was used to determine glucose consumption and relative glycogen content, and to determine the content of superoxide dismutase (SOD) and malondialdehyde (MDA). Western Blot method was used to determine the expression of oxidative stress-related proteins.Results:The content of sea-buckthorn polysaccharide was 88.46%. When the concentration of sea-buckthorn polysaccharide reached 800 μg/mL, the cell viability decreased significantly (P＜0.05). The subsequent safe dose was 400 μg/mL. Glucose consumption and relative glycogen content after seabuckthorn polysaccharide treatment were significantly increased (P＜0.05), SOD level reached (79.31±2.16) U/mg, MDA level reached (2.15±0.12) nmol/mg. After seabuckthorn polysaccharide treatment, the expression level of Nrf2 and HO-1 was significantly increased (P＜0.05), and the expression level of Keap1 was significantly reduced (P＜0.05).Conclusion:Hippophae rhamnoides polysaccharide can improve the abnormal glucose metabolism and oxidative stress level of insulin resistance cell model, and can improve insulin resistance by regulating the Nrf2/Keap1/HO-1 pathway.