Ginsenoside Rh2 promotes hepatic stellate cell ferroptosis and inactivation via regulation of IRF1-inhibited SLC7A11

Zhichao Lang; Suhui Yu; Yuhang Hu; Qiqi Tao; Jingnan Zhang; Haoyue Wang; Lei Zheng; Zhixian Yu; Jianjian Zheng

doi:10.1016/j.phymed.2023.154950

Ginsenoside Rh2 promotes hepatic stellate cell ferroptosis and inactivation via regulation of IRF1-inhibited SLC7A11

Phytomedicine. 2023 Sep:118:154950. doi: 10.1016/j.phymed.2023.154950. Epub 2023 Jul 4.

Authors

Zhichao Lang¹, Suhui Yu², Yuhang Hu¹, Qiqi Tao¹, Jingnan Zhang¹, Haoyue Wang¹, Lei Zheng³, Zhixian Yu⁴, Jianjian Zheng⁵

Affiliations

¹ Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
² Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
³ Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
⁴ Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: yzx515@163.com.
⁵ Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: zjj@wmu.edu.cn.

PMID: 37441987
DOI: 10.1016/j.phymed.2023.154950

Abstract

Background: Sustained liver fibrosis may lead to cirrhosis. Activated hepatic stellate cells (HSCs) are crucial for liver fibrosis development. Ferroptosis, a newly iron-dependent regulated cell death, has been demonstrated to be involved in HSC inactivation.

Purpose: Ginsenoside Rh2 (GRh2), a natural bioactive product derived from ginseng, has been shown to promote HSC inactivation. However, the effect of GRh2 on HSC ferroptosis remains unclear.

Methods: We explored the effects of GRh2 on liver fibrosis in vivo and in vitro. RNA-sequence analysis was performed in HSCs after GRh2 treatment. The crosstalk between ferroptotic HSCs and macrophages was also explored.

Results: GRh2 alleviated liver fibrosis in vivo. In vitro, GRh2 reduced HSC proliferation and activation via ferroptosis, with increased intracellular iron, reactive oxygen species, malondialdehyde and glutathione depletion. The expression of SLC7A11, a negative regulator of ferroptosis, was obviously reduced by GRh2. Interestingly, interferon regulatory factor 1 (IRF1), a transcription factor, was predicted to bind the promoter region of SCL7A11. The interaction between IRF1 and SCL7A11 was further confirmed by the results of chromatin immunoprecipitation and luciferase reporter assays. Furthermore, loss of IRF1 led to an increase in SCL7A11, which contributed to the suppression of HSC ferroptosis and the enhancement of HSC activation in GRh2-treated HSCs. Further studies revealed that GRh2-induced HSC ferroptosis contributed to the inhibition of macrophage recruitment via regulation of inflammation-related genes. Moreover, GRh2 caused a reduction in liver inflammation in vivo.

Conclusion: Collectively, GRh2 up-regulates IRF1 expression, resulting in the suppression of SLC7A11, which contributes to HSC ferroptosis and inactivation. GRh2 ameliorates liver fibrosis through enhancing HSC ferroptosis and inhibiting liver inflammation. GRh2 may be a promising drug for treating liver fibrosis.

Keywords: Ferroptosis; Ginsenoside Rh2; Hepatic stellate cells; IRF1/SLC7A11 signaling pathway; Liver fibrosis.

MeSH terms

Amino Acid Transport System y+ / metabolism
Ferroptosis*
Fibrosis
Hepatic Stellate Cells*
Humans
Inflammation / metabolism
Interferon Regulatory Factor-1 / metabolism
Interferon Regulatory Factor-1 / pharmacology
Iron / metabolism
Liver Cirrhosis / metabolism

Substances

ginsenoside Rh2
Interferon Regulatory Factor-1
Iron
SLC7A11 protein, human
Amino Acid Transport System y+
IRF1 protein, human