Background:Cholestatic liver disease (CLD) is a common disease of infancy, threatening infants’ health seriously. However, there is no effective drug to treat this disease.It is urgently to develop a new drug to overcome it. Polyamide-amine (PAMAM) dendrimer is a hyperbranched nano polymer, which has been found that has an anti-inflammatory effect recently. For this study, we aim to explore the protective effect and mechanism of PAMAM on CLD.Methods:In this study, a mouse model of cholestatic liver injury was created using ANIT,and TNF-α was utilized to stimulate human hepatocytes to investigate the protective effect and mechanism of 4.5th generation carboxyl-terminated PAMAM dendrimers (G4.5-COOH) in vivo and in vitro.Liver serum biochemistry, inflammatory, oxidative stress(OxS), endoplasmic reticulum(ER) stress and apoptosis indicators were determined.In addition, the effects of G4.5-COOH on PPAR-γ and PI3K/AKT/mTOR signaling pathway were studied. Data were analyzed by using one-way ANOVA. Results:We find the G4.5-COOH may inhibit TNF-α to damage hepatocytes and ameliorate the cholestatic liver injury. We also find that the protective effect of G4.5-COOH might be due to inhibition of P-Akt、P-mTOR expression by a mechanism that might be partly dependent on up-regulated functional expression of PPAR-γ.Conclusions:G4.5-COOH PAMAM dendrimer has a protective effect on CLD.