〔Abstract〕 To investigate the effects of polydatin on a high-fat diet-induced non-alcoholic fatty liver dis- ease (NAFLD) mouse model and hepatoma G2 (HepG2) cell model , and to reveal its potential molecular mecha- nisms . Methods Thirty 6-week-old male SPF C57BL/6J mice were randomly divided into a normal diet group and a high-fat diet group . After the NAFLD mouse model was established in the high-fat diet group , they were further divided into a model group and a polydatin treatment group . The polydatin treatment group was administered poly- datin by gavage at a dose of 250 mg/(kg ·d) for 10 weeks , during which body weight was monitored and oral glu- cose and insulin tolerance tests were performed . At the end of the experiment , a series of tests to evaluate the effects of polydatin on mouse liver weight , blood lipids , liver lipid accumulation , and liver injury markers were per- formed . The expression of G0 /G1 switch gene 2(G0S2) and adipose triglyceride lipase (ATGL) was measured by qRT-PCR and Western blot , and gene expression was further verified using immunohistochemical staining. The effects of polydatin on HepG2 cell activity was assessed by CCK-8 assay , lipid accumulation was observed by oil red O staining , and the expression of G0S2 and ATGL was detected by qRT-PCR and Western blot. Results Polydatin significantly reduced the body weight , liver weight , and serum and liver tissue levels of aspartate aminotransferase (AST) , alanine aminotransferase (ALT) , triglyceride (TG) , and total cholesterol (TC) in mice (P < 0. 05) , al- leviated pathological liver damage , decreased G0S2 expression (P < 0. 05) , and increased ATGL expression (P < 0. 05) . At the cellular level , polydatin reduced lipid droplet accumulation , improved lipid metabolism , decreased G0S2 expression ( P < 0. 05 ) , and increased ATGL expression ( P < 0. 05 ) . Even in cells with knockdown of G0S2 , polydatin still promoted fat decomposition (P < 0. 01) . Conclusion Polydatin promotes hepatic fat break- down by regulating the expression of G0S2 and ATGL , helping to alleviate metabolic disorders and liver damage in the NAFLD mouse model caused by a high-fat diet , offering a new strategy for treating NAFLD .