Abrus mollis is a widely used traditional Chinese medicine for treating acute and chronic hepatitis, steatosis, and fibrosis. It was found that the total flavonoid C-glycosides from Abrus mollis extract(AME) showed potent antioxidant, anti-inflammatory, and hepatoprotective activities. To further investigate the hepatoprotective effect of AME and its possible mechanisms, lipopolysaccharide(LPS)-induced liver injury models were applied in the current study. The results indicated that AME significantly attenuated LPS-induced lipid accumulation in mouse primary hepatocytes as measured by triglyceride(TG) and total cholesterol(TC) assays and Oil Red O staining. Meanwhile, AME exerted a protective effect on LPS-induced liver injury as shown by decreased liver index, serum aminotransferase levels, and hepatic lipid accumulation. Real-time PCR and immunoblot data suggested that AME reversed the LPS-mediated lipid metabolism gene expression, such as sterol regulatory element-binding protein-1(SREBP-1), fatty acid synthase(FAS), and acetyl-CoA carboxylase 1(ACC1). In addition, LPS-induced overexpression of activating transcription factor 4(ATF4), X-box-binding protein-1(XBP-1), and C/EBP homologous protein(CHOP) were dramatically reversed by AME. Furthermore, AME also decreased the expression of LPS-enhanced interleukin-6(IL-6) and cyclooxygenase-2(COX-2). Here, it is demonstrated for the first time that AME ameliorated LPS-induced hepatic lipid accumulation and that this effect of AME can be attributed to its modulation of hepatic de novo fatty acid synthesis. This study also suggested that the hepatoprotective effect of AME may be related to its down-regulation of unfolded protein response(UPR) activation. A was used widely in traditional Chinese medicine for treating acute and chronic hepatitis, steatosis, and fibrosis. It was found that the total flavonoid C-glycosides from Abrus mollis extract (AME) showed potent antioxidant, anti-inflammatory, and hepatoprotective activities. To further investigate the hepatoprotective effect of AME and its possible mechanisms, lipopolysaccharide (LPS) -induced liver injury models were applied in the current study. The results indicated that AME significantly attenuated LPS-induced lipid accumulation in mouse primary hepatocytes as measured by triglyceride ( TG) and total cholesterol (TC) assays and Oil Red O staining. Meanwhile, AME exerted a protective effect on LPS-induced liver injury as shown by decreased liver index, serum aminotransferase levels, and hepatic lipid accumulation. Real-time PCR and immunoblot data suggested that AME reversed the LPS-mediated lipid metabolism gene expression, such as sterol regulatory element-binding protein-1 ( SREBP-1), fatty acid synthase (FAS), and acetyl-CoA carboxylase 1 (ACC1). In addition, LPS- induced overexpression of activating transcription factor 4 (ATF4) ), and C / EBP homologous protein (CHOP) werebite reversed by AME. Furthermore, AME also decreased the expression of LPS-enhanced interleukin-6 (IL-6) and cyclooxygenase-2 demonstrated for the first time that AME ameliorated LPS-induced hepatic lipid accumulation and that this effect of AME can be attributed to its modulation of hepatic de novo fatty acid synthesis. This study also suggests that the hepatoprotective effect of AME may be related to its down -regulation of unfolded protein response (UPR) activation.