HBx facilitates ferroptosis in acute liver failure via EZH2 mediated SLC7A11 suppression

Abstract

Background Acute liver failure (ALF) is a syndrome of severe hepatocyte injury with high rate of mortality. Hepatitis B virus (HBV) infection is the major cause of ALF worldwide, however, the underlying mechanism by which HBV infection leads to ALF has not been fully disclosed. Methods D-GalN-induced hepatocyte injury model and LPS/D-GalN-induced ALF mice model were used to investigate the effects of HBV X protein (HBx) in vitro and in vivo, respectively. Cell viability and the levels of Glutathione (GSH), malondialdehyde (MDA) and iron were measured using commercial kits. The expression of ferroptosis-related molecules were detected by qRT-PCR and western blotting. Epigenetic modification and protein interaction were detected by chromatin immunoprecipitation (ChIP) assay and co-immunoprecipitation (co-IP), respectively. Mouse liver function was assessed by measuring aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The histological changes in liver tissues were monitored by hematoxylin and eosin (H&E) staining, and SLC7A11 immunoreactivity was assessed by immunohistochemistry (IHC) analysis. Results D-GalN triggered ferroptosis in primary hepatocytes. HBx potentiated D-GalN-induced hepatotoxicity and ferroptosis in vitro, and it suppressed SLC7A11 expression through H3K27me3 modification by EZH2. In addition, EZH2 inhibition or SLC7A11 overexpression attenuated the effects of HBx on D-GalN-induced ferroptosis in primary hepatocytes. The ferroptosis inhibitor ferrostatin-1 (Fer-1) protected against ALF and ferroptosis in vivo. By contrast, HBx exacerbates LPS/D-GalN-induced ALF and ferroptosis in HBx transgenic (HBx-Tg) mice. Conclusion HBx facilitates ferroptosis in ALF via EZH2/H3K27me3-mediated SLC7A11 suppression.

Maresin1 Protect Against Ferroptosis-Induced Liver Injury Through ROS Inhibition and Nrf2/HO-1/GPX4 Activation

“…It has been reported that the ferroptosis caused by D-GalN/LPS is associated with organ injury. D-GalN/LPS-induced liver injury was accompanied with iron accumulation and ROS production, substances that regulate ferroptosis -related signaling in hepatocytes are expected to contribute to the treatment of D-GalN/LPS-induced ALI ( Liu et al, 2021 ; Siregar et al, 2021 ).…”

LINC00114 stimulates growth and glycolysis of esophageal cancer cells by recruiting EZH2 to enhance H3K27me3 of DLC1

“…2 A). Based on the evidence that trimethylation of H3K27 causes gene silencing and transcriptional suppression [ 31 ], RIP assay was performed (Fig. 2 B), and the outcome suggested that LINC00114 was enriched in the immunoprecipitates under EZH2 and H3K27me3 antibody treatment.…”

The Role of Cystine/Glutamate Antiporter SLC7A11/xCT in the Pathophysiology of Cancer

“…Therefore, SLC7A11 prevents cells from undergoing ferroptosis by importing cystine and promoting GSH synthesis. In acute liver failure, overexpression of SLC7A11 plays a protective role in controlling the level of lipopolysaccharide-D-galactosamine-induced hepatocyte acute injury primarily through inhibiting ferroptosis ( 72 ). In contrast, SLC7A11 enhances ferroptosis in myofibroblast hepatic stellate cells, which can exacerbate liver injury ( 73 ).…”