Wedelolactone attenuates liver fibrosis and hepatic stellate cell activation by suppressing the Hippo pathway.

Abstract

Liver fibrosis is a commonly observed pathological phenomenon that occurs during the progression of various types of chronic liver diseases. The Hippo pathway is closely associated with the pathogenesis of liver fibrosis. Previous studies have shown that wedelolactone (WED) has a significant anti-hepatic fibrosis effect, whereas the target and mechanism underlying WED remain elusive. In this study, we found that WED significantly alleviated liver fibrosis and injury by inhibiting the expression of YAP and TAZ. In an in vitro model, WED suppressed the activation of hepatic stellate cells (HSCs) induced by TGF-β1, as well as the mRNA and protein expression of α-SMA, YAP, and TAZ. The allosteric regulation of YAP by WED was confirmed using MD and CETSA. Moreover, specific knockdown or inhibition of YAP did not enhance the suppressive effect of WED on HSC activation or protein expression associated with fibrosis. These findings demonstrated that the administration of WED effectively alleviated liver fibrosis by suppressing the Hippo/YAP/TAZ pathways. In addition, YAP activity may be regulated by WED via allosteric regulation.