School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong,510515, China.
Medical Laboratory of the Third affiliated Hospital of Shenzhen University, Shenzhen, 518001, China.
Phytomedicine. 2022 Jul;101:154117. doi: 10.1016/j.phymed.2022.154117. Epub 2022 Apr 20.
Liver fibrosis is a major disease that threatens people's health around the world. However, there is a lack of effective treatment to completely reverse liver fibrosis. Liver transplantation is currently the only curative option for patients with advanced cirrhosis. Ferroptosis is a newly discovered type of cell death and plays an important role in the process of liver fibrosis, but the specific mechanism needs to be clarified.
HYPOTHESIS/PURPOSE: To explore the regulatory mechanism of isoliquiritigenin (ISL) in the process of liver fibrosis and the relationship between Cav-1 and ferroptosis.
In this research, zebrafish, HSC-T6 cells, and mice were used as the research object. Different ROS probes to visually detect the content and distribution of ROS in live zebrafish and cells. Lentivirus and siRNA-mediated transfection techniques were used for the construction of Cav-1 overexpression and knockdown cell lines to verify the important role of Cav-1 in vitro.
Generally, we first elucidated that ISL relieved liver fibrosis by inducing hepatic stellate cells (HSCs) ferroptosis through repressing GPX4 expression and increasing the expression of TFR and DMT1, thus producing a large number of ROS, we also found that Cav-1 exerted its anti-hepatic fibrosis effect by promoting HSCs ferroptosis.
Our results have shown that Cav-1-mediated HSCs ferroptosis is necessary for ISL to play an anti-fibrotic effect in vitro and in vivo.
肝纤维化是一种严重威胁全球人类健康的疾病，但目前缺乏能够完全逆转肝纤维化的有效治疗手段。肝移植是目前治疗终末期肝硬化患者的唯一有效方法。铁死亡是一种新发现的细胞死亡方式，在肝纤维化过程中发挥着重要作用，但具体机制仍需进一步阐明。
假说/目的：探讨甘草查尔酮 B（ISL）在肝纤维化过程中的调控机制及 Cav-1 与铁死亡的关系。
本研究以斑马鱼、HSC-T6 细胞和小鼠为研究对象，利用不同的 ROS 探针直观地检测活体斑马鱼和细胞内 ROS 的含量和分布。利用慢病毒和 siRNA 介导的转染技术构建 Cav-1 过表达和敲低细胞系，验证 Cav-1 在体外的重要作用。
研究结果表明，ISL 通过抑制 GPX4 表达和增加 TFR 和 DMT1 的表达，从而产生大量 ROS，诱导肝星状细胞（HSCs）发生铁死亡，进而缓解肝纤维化。我们还发现，Cav-1 通过促进 HSCs 铁死亡发挥其抗肝纤维化作用。
我们的研究结果表明，Cav-1 介导的 HSCs 铁死亡是 ISL 在体外和体内发挥抗纤维化作用所必需的。
