Echinacoside Exerts Antihepatic Fibrosis Effects in High-Fat Mice Model by Modulating the ACVR2A-Smad Pathway

Scope Nonalcoholic steatohepatitis (NASH) is an increasingly common chronic liver disease in which hepatic fibrosis is the major pathological change. The transforming growth factor beta (TGF-beta)/mall mothers against decapentaplegic (Smad) signaling is the main effector of fibrosis. Although the antifibrotic effect of echinacoside (Ech) on the liver has been indicated previously, the cellular and molecular mechanisms remain unclear. This study aims to investigate both in vivo and in vitro antifibrotic properties of Ech. Methods and results Cell viability and scratch/wound assays show that Ech significantly inhibits the proliferation, migration, and activation of human hepatic stellate LX-2 cells. In mice with high-fat diet-induced hepatic fibrosis, Ech treatment attenuates the progression of liver injury, inflammation, and fibrosis. Furthermore, transcriptome analysis and subsequent functional validation demonstrate that Ech achieves antifibrotic effects by the activin receptor type-2A (ACVR2A)-mediated TGF-beta 1/Smad signaling pathway; ultimately, ACVR2A is demonstrated to be an important target for hepatic fibrosis by inhibiting and inducing the expression of ACVR2A in LX-2 cells. Conclusion Ech exerts potent antifibrotic effects by inhibiting the ACVR2A-mediated TGF-beta 1/Smad signaling axis and may serve as an alternative treatment for hepatic fibrosis.