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Published on: February 10, 2015
Wogonoside attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis through SOCS1/P53/SLC7A11
Guofang Liu1, Can Wei2, Siyu Yuan3
1School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
Abstract:
Wogonoside (WG) is a flavonoid chemical component extracted from Scutellaria baicalensis, which exerts therapeutic effects on liver diseases. Ferroptosis, a novel form of programmed cell death, regulates diverse physiological/pathological processes. In this study, we attempted to investigate a novel mechanism by which WG mitigates liver fibrosis by inducing ferroptosis in hepatic stellate cells (HSCs). A CCl4 -induced mouse liver fibrosis model and a rat HSC line were employed for in vivo and in vitro experiments, both treated with WG. Firstly, the levels of the fibrotic markers α-smooth muscle actin (α-SMA) and α1(I)collagen (COL1α1) were effectively decreased by WG in CCl4 -induced mice and HSC-T6 cells. Additionally, mitochondrial condensation and mitochondrial ridge breakage were observed in WG-treated HSC-T6 cells. Furthermore, ferroptotic events including depletion of SLC7A11, GPX4 and GSH, and accumulation of iron, ROS and MDA were discovered in WG-treated HSC-T6 cells. Intriguingly, these ferroptotic events did not appear in hepatocytes or macrophages. WG-elicited HSC ferroptosis and ECM reduction were dramatically abrogated by ferrostatin-1 (Fer-1), a ferroptosis inhibitor. Importantly, our results confirm that SOCS1/P53/SLC7A11 is a signaling pathway which promotes WG attenuation of liver fibrosis. On the contrary, WG mitigated liver fibrosis and inducted HSC-T6 cell ferroptosis were hindered by SOCS1 siRNA and pifithrin-α (PFT-α). These findings demonstrate that SOCS1/P53/SLC7A11-mediated HSC ferroptosis is associated with WG alleviating liver fibrosis, which provides a new clue for the treatment of liver fibrosis.
Insights
Wogonoside (WG) alleviates liver fibrosis by inducing ferroptosis, a specific cell death, in hepatic stellate cells (HSCs). This mechanism involves the SOCS1/P53/SLC7A11 pathway, offering a new therapeutic strategy for liver fibrosis.
Area of Science:
- Hepatology and Cell Death Research
- Natural Product Chemistry
- Molecular Biology
Background:
- Liver fibrosis is a significant health concern with limited treatment options.
- Ferroptosis, a regulated form of cell death, plays a role in various pathological processes, including liver disease.
- Wogonoside (WG), a flavonoid from Scutellaria baicalensis, shows therapeutic potential for liver conditions.
Purpose of the Study:
- To investigate the mechanism by which Wogonoside (WG) mitigates liver fibrosis.
- To determine if WG induces ferroptosis specifically in hepatic stellate cells (HSCs).
- To elucidate the signaling pathway involved in WG-mediated mitigation of liver fibrosis.
Main Methods:
- In vivo study using a carbon tetrachloride (CCl4)-induced mouse liver fibrosis model.
- In vitro study using a rat HSC line (HSC-T6) treated with WG.
- Analysis of fibrotic markers (α-SMA, COL1α1), mitochondrial morphology, ferroptotic indicators (SLC7A11, GPX4, GSH, iron, ROS, MDA), and signaling pathways (SOCS1/P53/SLC7A11).
- Use of ferroptosis inhibitor (Fer-1), SOCS1 siRNA, and pifithrin-α (PFT-α) to validate the mechanism.
Main Results:
- WG treatment significantly reduced fibrotic markers (α-SMA, COL1α1) in both mouse models and HSCs.
- WG induced characteristic ferroptotic events in HSCs, including mitochondrial changes and altered levels of key ferroptosis markers.
- These ferroptotic effects were specific to HSCs and were abrogated by the ferroptosis inhibitor ferrostatin-1.
- The SOCS1/P53/SLC7A11 pathway was identified as crucial for WG's antifibrotic effects, with inhibition of this pathway hindering WG's efficacy.
Conclusions:
- Wogonoside effectively mitigates liver fibrosis by inducing ferroptosis in hepatic stellate cells.
- The SOCS1/P53/SLC7A11 signaling pathway mediates the antifibrotic effects of Wogonoside.
- These findings highlight Wogonoside as a potential therapeutic agent for liver fibrosis through targeted induction of HSC ferroptosis.
