Yuan Ziqiao, Meng Jiahui, Shen Xuange, Wang Meifei, Yu Yun, Shi Le, Li Ya-Lan, Hassan Hozeifa M, Li Haixia, He Zhang-Xu, Qin Tingting
Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
J Agric Food Chem. 2024 Oct 3. doi: 10.1021/acs.jafc.4c05529.
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. FMN administration protected mice from BDL or CCl-induced liver fibrosis. 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.
芒柄花黄素（FMN）是一种主要来源于豆科植物的异黄酮，是一种天然次生代谢产物，在多种慢性疾病的调节中具有重要的药理作用。本研究旨在探讨FMN对肝纤维化的影响并阐明其潜在机制。给予FMN可保护小鼠免受胆管结扎（BDL）或四氯化碳（CCl）诱导的肝纤维化。实验结果显示FMN对肝星状细胞（HSC）激活具有介导的抑制作用。转录组分析表明，YAP沉默及随后的HSC衰老可能是FMN介导的抗纤维化结果的原因。此外，FMN抑制EZH2及其底物H3K27me3，这对YAP激活和HSC衰老至关重要。值得注意的是，EZH2过表达逆转了FMN对影响HSC衰老的YAP的潜在治疗作用。我们的研究表明，FMN可能通过抑制EZH2/YAP轴和促进HSC衰老来减轻肝纤维化。总之，这些发现为FMN在肝纤维化治疗中的潜在治疗靶点提供了见解。
