Caffeic acid phenethyl ester (CAPE) has been reported to possess the hepatoprotective effect. This study was to investigate the mechanism underlying CAPE against liver fibrosis in a liver fibrosis model induced by toxic carbon tetrachloride (CCI4) in male Sprague-Dawley rats and in vitro in CAPE (5 mu M, 10 mu M, 15 mu M) treated hepatic stellate cells (HSC-T6). We found that CAPE treatment remarkably attenuated CCI4-induced liver fibrosis by blocking the activation of HSCs as determined by the expression alternation of transforming growth factor (TGF)-beta 1, phosphorylated Smad3 (p-Smad3), collage I, alpha-smooth muscle actin (alpha-SMA), matrix metalloproteinases (MMPs) 2, tissue inhibitor of matrix metalloproteinases (TIMPs) 1. The hepatoprotective effects of CAPE were also associated with upregulation of autophasomes in HSCs as determined by transmission electron microscopy (TEM) detection. The in vitro study further confrimed that CAPE attenuated liver fibrogenesis via inducing authophagic markers including LC3, ATG5, Beclin 1 expressions, while inhibiting AKT/mTOR signaling in HSC-T6 cells. Thus, the protective effects of CAPE against liver fibrosis might due to the inhibition of TGF-beta 1/Smad3 signaling and induction of authophagy in HSCs. (C) 2017 Published by Elsevier Inc.