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

作者：Jiawei Zhao, Dongsheng Bai, Lei Qi, Wangjia Cao, Jiaying Du, Chunyang Gu, Chen Zhou, Yuan Gao, Lulu Zhang, Yue Zhao, Na Lu · 发表于：British Journal of Pharmacology · 年份：2022 · DOI：10.1111/bph.15997 · 被引用次数：23 · 研究领域：Liver physiology and pathology、Liver Disease Diagnosis and Treatment、Hepatocellular Carcinoma Treatment and Prognosis

BACKGROUND AND PURPOSE: 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: ) 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 RESULTS: 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. CONCLUSION AND IMPLICATIONS: GL-V9 exerted potent anti-fibrotic effects both in vivo and in vitro by stabilizing GATA4, thereby promoting the sen...