Astragaloside IV Synergizes with Ferulic Acid to Alleviate Hepatic Fibrosis in Bile Duct-Ligated Cirrhotic Rats

Due to the multi-factorial etiology of hepatic fibrosis, multi-target therapeutics based on combinatory drugs is known to be a promising strategy for the disease. The present study attempted to test the hypothesis that astragaloside IV combined with ferulic acid synergistically inhibits activation of hepatic stellate cells in vivo. Bile duct-ligated rats were treated with astragaloside IV or/and ferulic acid for 28 days. Liver fibrosis was measured by histological examination. The oxidative stress-related biomarkers were measured with spectrophotometry. Expressions of mRNA and protein were measured by real-time PCR and Western blotting. Bile duct-ligated rat treatment with astragaloside IV and ferulic acid in combination resulted in synergistic alleviation of hepatic fibrosis. Simultaneously, activation of hepatic stellate cells was significantly inhibited by the combination therapy when compared with astragaloside IV or ferulic acid alone. Interestingly, astragaloside IV, but not ferulic acid, induced accumulation of Nrf2 in the nucleus, synthesized antioxidant enzymes through negative regulation of glycogen synthase kinase-3β, scavenged reactive oxygen species, and, in turn, suppressed hepatic stellate cells activation in bile duct-ligated rats. Conversely, ferulic acid, but not astragaloside IV, suppressed TGF-β1 and its receptors expression, which resulted in downregulation of Smad3 and Smad4. These findings suggest that the combination of astragaloside IV and ferulic acid synergistically induces deactivation of hepatic stellate cells through inhibition of the TGF-β pathway and activation of the Nrf2 pathway, and suggest that combination of astragaloside IV and ferulic acid is a promising candidate for the treatment of hepatic fibrosis.