人参皂苷 Rg3 通过表观遗传调控 ACSL4 促进肝星状细胞铁死亡，抑制肝纤维化进展。
Ginsenoside Rg3 promotes hepatic stellate cell ferroptosis by epigenetically regulating ACSL4 to suppress liver fibrosis progression.
机构信息
Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Lane, Wenzhou 325000, Zhejiang, PR China; Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo 315300, Zhejiang, PR China.
Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Lane, Wenzhou 325000, Zhejiang, PR China.
出版信息
Phytomedicine. 2024 Feb;124:155289. doi: 10.1016/j.phymed.2023.155289. Epub 2023 Dec 16.
BACKGROUND
Ginsenoside Rg3 (G-Rg3), extracted from Panax notoginseng, possesses hepatoprotective properties. Hepatic stellate cells (HSCs) activation is responsible for liver fibrosis. Recent studies have reported the suppressive effects of G-Rg3 on HSC activation and proliferation. Ferroptosis is a novel iron regulated cell death. ACSL4, a key indicator of ferroptosis, is commonly methylated in various diseases.
PURPOSE
However, the role of ACSL4 methylation-mediated HSC ferroptosis in G-Rg3 inhibition of hepatic fibrosis needs to be explored.
METHODS
Effects of G-Rg3 on inhibiting fibrosis were evaluated in vivo and in vitro. The impact of G-Rg3 on HSC ferroptosis was assessed in vitro. Furthermore, the expression of ACSL4, ACSL4 methylation and microRNA-6945-3p (miR-6945-3p) levels were determined.
RESULTS
G-Rg3 significantly alleviated CCl-induced liver fibrosis, accompanied by collagen downregulation. In vitro, G-Rg3 contributed to HSC inactivation, leading to decreased collagen production. G-Rg3 induced HSC ferroptosis, characterized by increased iron accumulation, depletion of glutathione, malondialdehyde levels, and generation of lipid reactive oxygen species. Moreover, G-Rg3 promoted ACSL4 demethylation and restored its expression. Notably, DNMT3B counteracted the effect of G-Rg3-mediated inhibition of ACSL4 methylation and was targeted by miR-6945-3p. Further investigations revealed that G-Rg3 suppressed ACSL4 methylation through miR-6945-3p-mediated DNMT3B inhibition. Consistent with this, miR-6945-3p inhibition reversed G-Rg3-induced ACSL4 expression and HSC ferroptosis.
CONCLUSION
G-Rg3 inhibits ACSL4 methylation by miR-6945-3p-mediated DNMT3B inhibition, thereby promoting HSC ferroptosis and mitigating liver fibrosis.
背景
从三七中提取的人参皂苷 Rg3（G-Rg3）具有保肝作用。肝星状细胞（HSCs）激活是肝纤维化的原因。最近的研究报告称，G-Rg3 对 HSC 激活和增殖具有抑制作用。铁死亡是一种新型的铁调节细胞死亡。酰基辅酶 A 合成酶家族成员 4（ACSL4）是铁死亡的一个关键指标，在各种疾病中通常被甲基化。
目的
然而，ACSL4 甲基化介导的 HSC 铁死亡在 G-Rg3 抑制肝纤维化中的作用需要进一步探讨。
方法
在体内和体外评估 G-Rg3 抑制纤维化的效果。在体外评估 G-Rg3 对 HSC 铁死亡的影响。此外，测定 ACSL4、ACSL4 甲基化和 microRNA-6945-3p（miR-6945-3p）的表达水平。
结果
G-Rg3 显著减轻 CCl4 诱导的肝纤维化，同时下调胶原表达。体外，G-Rg3 促进 HSC 失活，导致胶原产生减少。G-Rg3 诱导 HSC 铁死亡，表现为铁积累增加、谷胱甘肽耗竭、丙二醛水平升高和脂质活性氧生成。此外，G-Rg3 促进 ACSL4 去甲基化并恢复其表达。值得注意的是，DNMT3B 抵消了 G-Rg3 介导的 ACSL4 甲基化抑制作用，并且是 miR-6945-3p 的靶标。进一步研究表明，G-Rg3 通过 miR-6945-3p 介导的 DNMT3B 抑制抑制 ACSL4 甲基化。与此一致，miR-6945-3p 抑制逆转了 G-Rg3 诱导的 ACSL4 表达和 HSC 铁死亡。
结论
G-Rg3 通过 miR-6945-3p 介导的 DNMT3B 抑制抑制 ACSL4 甲基化，从而促进 HSC 铁死亡和减轻肝纤维化。
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