Aucubin inhibits hepatic stellate cell activation through stimulating Nrf2/Smad7 axis.

Aim: Liver fibrosis may develop into end-stage liver disease if left unprevented. The study is attempting to identify a compound to ameliorate liver fibrosis progression with high efficiency and low toxicity, as well as to analyze its potential molecular mechanism.

Methods: The drug screening was performed using human hepatic stellate cell line LX-2 for identifying the compound as collagen I inhibitor. Primary Human hepatic stellate cells and LX-2 cell line were used to detect the antifibrotic function activity and molecular mechanism analysis in vitro. The CCl-induced mouse experimental model was used to measure the amelioration in liver fibrosis.

Results: This study identified Aucubin, a natural compound, as a candidate for anti-liver fibrosis. Besides, Aucubin could inhibit the collagen I and α-SMA expressions in LX-2 cells and primary human hepatic stellate cells, as well as the cell proliferation. In terms of mechanism, Aucubin could upregulate Smad7 in hepatic stellate cells in a dose-dependent manner and block TGF-β signaling. We also found that Nrf2 might be a direct target for the action of Aucubin, whose activation was necessary for Smad7 upregulation. In an in-vivo mouse model, Aucubin efficiency ameliorated the progression of CCl-induced liver fibrosis, and reduced the hepatic levels of collagen deposition, transaminase and inflammatory cytokines.

Conclusion: Capable of inhibiting the activation of hepatic stellate cells in vitro and in vivo, Aucubin may be a potential therapeutic candidate for liver fibrosis, which is dependent on the suppression of TGF-β signaling through stimulating Nrf2/Smad7 axis.