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

Abstract

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 CCl 4 . 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 CCl 4 ‐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 Attenuates Fibrotic Hepatic Injury Through Mediating Lysine Crotonylation

“…Besides, histopathological changes were also used to analyze the degree of liver fibrosis. 22 H&E, Masson trichrome and PSR were all demonstrated sorafenib repressed the hepatocellular necrosis, inflammatory infiltration and liver fibrosis. Moreover, the typical hallmark of fibrosis was the activation of hepatic stellate cells to induce Acta2 expression.…”

High Dietary Organic Iron Supplementation Decreases Growth Performance and Induces Oxidative Stress in Broilers

“…The activities of total superoxide dismutase (T-SOD), T-AOC, and MDA concentrations in the livers of 42-day-old broilers were detected by the corresponding commercial kits purchased from Nanjing Jiancheng Bioengineering institute (Nanjing, China), according to the manufacturer's instructions. Liver Fe contents were detected according to the method reported by Yuan et al [25]. The serum biochemical parameters with the corresponding commercial kit number are listed in Table 3.…”

Role of Ferroptosis in Fibrotic Diseases

“…70 In addition, sorafenib was also reported to trigger HSC ferroptosis via hypoxia-inducible factor (HIF)-1α/SLC7A11 signaling, which attenuates liver injury and fibrosis in a mouse model of liver fibrosis induced by CCl 4 . 71 An E3 ubiquitin ligament TRIM26 was decreased in fibrotic liver tissues, which was originally identified as a tumor suppressor in hepatocellular carcinoma. A recent study found that TRIM26 promotes HSCs ferroptosis to mitigate liver fibrosis through mediating the ubiquitination of SLC7A11, the subunit in xCT system for lipid ROS scavenging.…”