Lawsone can suppress liver fibrosis by inhibition of YAP signaling and induction of CYGB expression in hepatic stellate cells

Abstract

Liver fibrosis, which eventually leads to cirrhosis, is characterized by excessive accumulation of type I collagen (COL1A), mainly derived from activated hepatic stellate cells (HSCs). Currently, there is no clinical treatments that can directly address this condition. The objectives of this study were to identify a compound that can suppress HSC activation and elucidate the molecular mechanism underlying its action. Chemical screening of antifibrogenic drugs was performed using a human COL1A2 promoter-based chemical screening system. Upon screening 1880 compounds, lapachol (a 1,4-naphtoquinone analog) was identified as an inhibitor of HSC activation. Among the tested 1,4-naphtoquinone analogs, we found that lawsone (LWS) robustly inhibited HSC activation by suppressing the expression of alpha-smooth muscle actin (αSMA) and enhancing the expression of cytoglobin (CYGB). LWS attenuated the assembly of actin filament and reduced the levels of Yes-associated protein (YAP) in HSCs with and without transforming growth factor-beta (TGFβ) exposure. Overexpression of YAP enhanced mRNA and protein levels of COL1A and αSMA in HSCs, but not of CYGB. These results strongly indicate that LWS suppresses HSC activation by decreasing YAP protein levels, suggesting that LWS induces CYGB expression independently of YAP. Furthermore, LWS alleviated thioacetamide- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced liver fibrosis by reducing YAP levels in the liver. This study provided evidence that LWS suppresses liver fibrosis by inhibiting YAP signaling and inducing CYGB expression.