Formononetin Mitigates Liver Fibrosis via Promoting Hepatic Stellate Cell Senescence and Inhibiting EZH2/YAP Axis

作者：Ziqiao Yuan, Jiahui Meng, Xuange Shen, Meifei Wang, Yun Yu, Le Shi, Yalan Li, Hozeifa Mohamed Hassan, Haixia Li, Zhangxu He, Tingting Qin · 发表于：Journal of Agricultural and Food Chemistry · 年份：2024 · DOI：10.1021/acs.jafc.4c05529 · 被引用次数：5 · 研究领域：Liver physiology and pathology、Liver Disease Diagnosis and Treatment

Formononetin (FMN), an isoflavone mainly derived from leguminous plants, is a natural secondary metabolite with valuable pharmacological effects in the regulation of numerous chronic diseases. This study aimed to investigate the influence of FMN on liver fibrosis and clarify the underlying mechanisms. In vivo FMN administration protected mice from BDL or CCl 4 -induced liver fibrosis. In vitro experimental findings revealed the FMN-mediated inhibitory effects on hepatic stellate cell (HSC) activation. Transcriptome analyses showed that YAP silencing and the subsequent HSC senescence might be responsible for the FMN-mediated antifibrotic outcomes. Furthermore, FMN suppressed EZH2 and its substrate H3K27me3, which are essential for YAP activation and HSC senescence. Remarkably, EZH2 overexpression reversed the FMN potential therapeutic effects on YAP that impact HSC senescence. Our study demonstrated that FMN potentially mitigated hepatic fibrosis by inhibiting EZH2/YAP axis and promoting HSC senescence. Together, these findings provide insights into the prospective therapeutic targets of FMN in liver fibrosis management.