Objective:This study aimed to investigate the potential of quercetin(Que)in ameliorating non-alcoholic fatty liver disease (NAFLD)induced by a high-fat diet(HFD)through the modulation of endoplasmic reticulum stress(ERS)in rats. Methods: Feeding SD rats with high-fat diet(HFD)for 8 weeks to establish the NAFLD model,then randomly divided into the HFD group,HFD + low-dose Que group(25 mg/kg),and HFD + high-dose Que group(50 mg/kg). Another group of rats fed normal diet served as the control group. During the administration period,monitoring of rat body weight and food intake was conducted. After continuing feeding for 8 weeks,serum levels of total cholesterol(TC),triglycerides(TG),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C),alanine aminotransferase(ALT),aspartate aminotransferase(AST),as well as changes in TC and TG content in liver tissue of each group were detected. Histopathological changes in rat liver tissue were observed by hematoxylin -eosin (HE)staining,oil red O staining,and Masson’s staining. Blood glucose levels were measured using a glucometer,and rat glucose tolerance was assessed by glucose tolerance test. Fasting insulin levels in each group of rats were detected using enzyme-linked immunosorbent assay(ELISA)kits. Real-time fluorescent quantitative PCR was used to detect the expression changes of ERS-related genes Bip,Atf6,Atf4,Xbp-1s,and Chop in rat liver tissue of each group. Western blot was used to detect the expression changes of ERS-related proteins BiP,CHOP,ATF4,ATF6,XBP-1s,and XBP-1u in rat liver tissue of each group. Results:Throughout the experiment, no significant differences in food intake and body weight were observed among the four groups. Compared to the control group,the HFD group exhibited increased serum levels of triglycerides(TG),total cholesterol(TC),low-density lipoprotein-cholesterol(LDL-C), glutamic oxalacetic transaminase(AST),and glutamic-pyruvic transaminase(ALT),along with decreased high-density lipoprotein-cholesterol(HDL-C)levels(P < 0.05). In the low-dose Que group,serum levels of TG,TC,LDL-C,AST,and ALT were significantly reduced compared to the HFD group(P < 0.05). Similarly,the high-dose Que group showed decreased serum levels of TG,TC,AST, and ALT compared to the HFD group(P < 0.05). In the HFD group,the liver exhibited enlargement and increased absolute weight, with prominently swollen hepatocytes,marked vacuolization,and accumulated lipid droplets. Additionally,increased collagen deposition,insulin resistance,and impaired glucose tolerance were observed in the HFD group. However,these alterations were reversed in both low-and high-dose Que groups. The results of RT-qPCR and Western blot showed that compared to the control group, the mRNA expression of Bip,Atf6,Atf4,Xbp-1s,and Chop in the liver tissue of rats in the HFD group significantly increased,and the protein expression of BiP,CHOP,ATF4,ATF6,and XBP-1s also significantly increased. Compared to the HFD group,the mRNA expression of Bip,Atf6,Atf4,Xbp-1s,and Chop in the liver tissue of rats in the low-and high-dose Que groups decreased,and the protein expression of BiP,CHOP,ATF4,ATF6,and XBP -1s also significantly decreased. Conclusion:Que treatment attenuates HFD-induced aberrant lipid metabolism,impaired glucose tolerance,and hepatic lipid deposition in NAFLD rats,with modulation of the ERS-related pathway potentially playing a critical role.