GL-V9 alleviates liver fibrosis via triggering GATA4-mediated senescence in activated hepatic stellate cells.

BACKGROUND AND PURPOSE
Liver fibrosis is an important risk factor for progression from chronic liver injury to hepatocellular carcinoma. Clinically, there is a serious lack of therapeutic drugs for liver fibrosis. Previous studies have confirmed that GL-V9, a new synthesized flavonoid derivative, exhibits anti-inflammatory activity, but whether it has anti-hepatic fibrosis remains unclear. This study aims to investigate the anti-fibrotic activities and potential mechanisms of GL-V9.


EXPERIMENTAL APPROACH
Bile duct ligation (BDL) and carbon tetrachloride (CCl4 ) challenge were used to assess anti-fibrotic effects of GL-V9 in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX2 also served as an in vitro liver fibrosis model. Cellular functions and molecular mechanism were analyzed using senescence-associated beta-galactosidase staining, real-time PCR, western blotting, immunofluorescence and co-immunoprecipitation.


KEY RESULTS
GL-V9 attenuated hepatic histopathological injury, collagen accumulation and decreased the expression of fibrotic genes in vivo. In vitro, GL-V9 promoted senescence and inhibited the expression of fibrogenic genes in HSCs. Mechanistic studies revealed that GL-V9 induced senescence by upregulating GATA4 expression in HSCs. Further studies confirmed that GL-V9 stabilized GATA4 by promoting autophagic degradation of P62.


CONCLUSION AND IMPLICATIONS
GL-V9 exerted potent anti-fibrotic effect both in vivo and in vitro by stabilizing GATA4, thereby promoting the senescence of HSCs, avoiding its activation and ultimately inhibiting liver fibrosis. This indicated that the flavonoid GL-V9 is a potential therapeutic candidate for the treatment of liver fibrosis.