Sorafenib and fluvastatin synergistically alleviate hepatic fibrosis via inhibiting the TGFβ1/Smad3 pathway

Abstract

Background: Effective strategies for the treatment of hepatic fibrosis are urgently in need.

Aims: To investigate the effect of the co-treatment of sorafenib and fluvastatin on hepatic fibrosis and the underlying mechanisms.

Methods: A diethylnitrosamine-induced hepatic fibrosis rat model was used to evaluate the anti-fibrosis effect. Epithelial mesenchymal transition (EMT) of hepatocytes and hepatic stellate cells (HSCs) in response to sorafenib and fluvastatin was explored. A co-treatment effect on TGFβ1 expression was explored in the Kupffer cells of rats. The effect of co-treatment on the regulation of the TGFβ1/Smad3 pathway was investigated in both L02 cells and LX-2 cells.

Results: Sorafenib and fluvastatin synergistically reduced collagen content, α-SMA expression, lamin level, and hyaluronic acid level in the rat hepatic model. Combination treatment significantly inhibited the expression of mesenchymal markers and promoted the expression of epithelial markers in hepatocytes. Co-treatment statistically suppressed the production of TGFβ1 in Kupffer cells. Suppression of EMT in parallel with alleviated up-regulation of fibronectin and α-SMA expression was observed in TGFβ1-activated LX-2 cells. Mechanistically, sorafenib plus fluvastatin blocked the TGFβ1/Smad3 signaling pathway via inhibiting phosphorylation of TβR II in hepatocytes and HSCs.

Conclusions: Sorafenib and fluvastatin synergistically alleviated diethylnitrosamine-induced hepatic fibrosis in rats. Sorafenib plus fluvastatin may be a potential combination treatment for hepatic fibrotic diseases.

Keywords: Epithelial mesenchymal transition; Fluvastatin; Hepatic fibrosis; Sorafenib; TGFβ1.