The flavonoid GL-V9 alleviates liver fibrosis by triggering senescence by regulating the transcription factor GATA4 in activated hepatic stellate cells

Liver fibrosis is a critical risk factor for the progression from chronic liver injury to hepatocellular carcinoma. Clinically, there is a lack of therapeutic drugs for liver fibrosis. Previous studies have confirmed that GL-V9, a newly synthesized flavonoid derivative, exhibits anti-inflammatory activity, but whether it has anti-hepatic fibrosis actions remains unclear. This study aimed to investigate the anti-fibrotic activities and potential mechanisms of GL-V9. Experimental approach: Bile duct ligation (BDL) and carbon tetrachloride (CCl4 ) challenges were used to assess the anti-fibrotic effects of GL-V9 in vivo. Mouse primary hepatic stellate cells (pHSCs) and the human HSC line LX2 also served as a liver fibrosis model in vitro. Cellular functions and molecular mechanism were analysed using senescence-associated beta-galactosidase staining, real-time PCR, western blotting, immunofluorescence, and co-immunoprecipitation. Key

Liver fibrosis is a critical risk factor for the progression from chronic liver injury to hepatocellular carcinoma. Clinically, there is a lack of therapeutic drugs for liver fibrosis. Previous studies have confirmed that GL-V9, a newly synthesized flavonoid derivative, exhibits anti-inflammatory activity, but whether it has anti-hepatic fibrosis actions remains unclear. This study aimed to investigate the anti-fibrotic activities and potential mechanisms of GL-V9. Experimental approach: Bile duct ligation (BDL) and carbon tetrachloride (CCl4 ) challenges were used to assess the anti-fibrotic effects of GL-V9 in vivo. Mouse primary hepatic stellate cells (pHSCs) and the human HSC line LX2 also served as a liver fibrosis model in vitro. Cellular functions and molecular mechanism were analysed using senescence-associated beta-galactosidase staining, real-time PCR, western blotting, immunofluorescence, and co-immunoprecipitation. Key

GL-V9 attenuated hepatic histopathological injury and collagen accumulation, as well as decreasing the expression of fibrotic genes in vivo. GL-V9 promoted senescence and inhibited the expression of fibrogenic genes in HSCs in vitro. 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.