Journal Article

Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF‐1α/SLC7A11 pathway

Yuan, Siyu, Li, Jiahao, Cai, Shiyi, Wei, Can, Liu, Guofang, Zhang, Lijun, Fang, Ling, Li, Lingling

2022

Overview

Objectives Evidences demonstrate that sorafenib alleviates liver fibrosis via inhibiting HSC activation and ECM accumulation. The underlying mechanism remains unclear. Ferroptosis, a novel programmed cell death, regulates diverse physiological/pathological processes. In this study, we aim to investigate the functional role of HSC ferroptosis in the anti‐fibrotic effect of sorafenib. Materials and Methods The effects of sorafenib on HSC ferroptosis and ECM expression were assessed in mouse model of liver fibrosis induced by CCl4. In vitro, Fer‐1 and DFO were used to block ferroptosis and then explored the anti‐fibrotic effect of sorafenib by detecting α‐SMA, COL1α1 and fibronectin proteins. Finally, HIF‐1α siRNA, plasmid and stabilizers were applied to assess related signalling pathway. Results Sorafenib attenuated liver injury and ECM accumulation in CCl4‐induced fibrotic livers, accompanied by reduction of SLC7A11 and GPX4 proteins. In sorafenib‐treated HSC‐T6 cells, ferroptotic events (depletion of SLC7A11, GPX4 and GSH; accumulation iron, ROS and MDA) were discovered. Intriguingly, these ferroptotic events were not appeared in hepatocytes or macrophages. Sorafenib‐elicited HSC ferroptosis and ECM reduction were abrogated by Fer‐1 and DFO. Additionally, both HIF‐1α and SLC7A11 proteins were reduced in sorafenib‐treated HSC‐T6 cells. SLC7A11 was positively regulated by HIF‐1α, inactivation of HIF‐1α/SLC7A11 pathway was required for sorafenib‐induced HSC ferroptosis, and elevation of HIF‐1α could inhibit ferroptosis, ultimately limited the anti‐fibrotic effect. Conclusions Sorafenib triggers HSC ferroptosis via HIF‐1α/SLC7A11 signalling, which in turn attenuates liver injury and fibrosis. Sorafenib triggers hepatic stellate cell ferroptosis by inhibiting the HIF‐1α/SLC7A11 pathway to attenuate liver fibrosis. Treatment with sorafenib induces a decrease of HIF‐1α, which in turn reduces SLC7A11 expression in HSCs. Then leads to GPX4, GSH depletion and ROS excess, and ultimately induces HSC ferroptosis and ECM reduction.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Accumulation / Actins - metabolism / Amino Acid Transport System y+ - metabolism / Animals / Antibodies / Apoptosis / Attenuation / Carbon tetrachloride / Cell culture / Cell death / Cell Line / Collagen / Collagen Type I - metabolism / Cytotoxicity / Depletion / Drug dosages / Extracellular matrix / Ferroptosis / Ferroptosis - drug effects / Fibronectin / Fibrosis / Hepatic Stellate Cells - drug effects / Hepatic Stellate Cells - metabolism / Hepatic Stellate Cells - pathology / Hepatocytes / Hepatocytes - drug effects / Hepatocytes - metabolism / Hepatocytes - pathology / HIF‐1α/SLC7A11 / HSCs / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Inactivation / Kinases / Liver / Liver Cirrhosis - drug therapy / Liver Cirrhosis - pathology / Liver diseases / liver fibrosis / Macrophages / Macrophages - drug effects / Macrophages - metabolism / Macrophages - pathology / Male / Mice / Mice, Inbred C57BL / Models, Biological / Morphology / Original / Protein Stability - drug effects / Proteins / Quantitative analysis / Reduction / Signal transduction / Signal Transduction - drug effects / Signaling / siRNA / sorafenib / Sorafenib - pharmacology / Sorafenib - therapeutic use