Apamin is an integral part of bee venom, as a peptide component. It has long been known as a highly selective block Ca2+-activated K (SK) channels. However, the cellular mechanism and anti-fibrotic effect of apamin in TGF-beta 1-induced hepatocytes have not been explored. In the present study, we investigated the anti-fibrosis or anti-EMT mechanism by examining the effect of apamin on TGF-beta 1-induced hepatocytes. AML12 cells were seeded at similar to 60% confluence in complete growth medium. Twenty-four hours later, the cells were changed to serum free medium containing the indicated concentrations of apamin. After 30 min, the cells were treated with 2 ng/ml of TGF-beta 1 and co-cultured for 48 h. Also, we investigated the effects of apamin on the CCl4-induced liver fibrosis animal model. Treatment of AML12 cells with 2 ng/ml of TGF-beta 1 resulted in loss of E-cadherin protein at the cell-cell junctions and concomitant increased expression of vimentin. In addition, phosphorylation levels of ERK1/2, Akt, Smad2/3 and Smad4 were increased by TGF-beta 1 stimulation. However, cells treated concurrently with TGF-beta 1 and apamin retained high levels of localized expression of E-cadherin and showed no increase in vimentin. Specifically, treatment with 2 mu g/ml of apamin almost completely blocked the phosphorylation of ERK1/2, Aid, Smad2/3 and Smad4 in AML12 cells. In addition, apamin exhibited prevention of pathological changes in the CCl4-injected animal models. These results demonstrate the potential of apamin for the prevention of EMT progression induced by TGF-beta 1 in vitro and CCl4-injected in vivo. (C) 2014 Elsevier Inc. All rights reserved.