PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis

Abstract

Background & AimsDeletion of 15 to 21 nucleotides covering the preS1 start codon frequently occurs in chronic hepatitis B patients with HBV genotype C and has been reported to be related to progression to HCC. However, underlying mechanism causing the distinct phenotype of this HBV variant remains largely unknown. We sought to investigate the mechanism by which preS1Del is related to liver disease progression and enhanced HBV replication, focusing on the ER stress. MethodsThe effects of HBV replicative capacity, ER stress signaling, inflammation, cell death, and tumorigenesis resulting from PreS1 deletions were investigated through in vitro and in vivo experiments. Inhibitors of the IRE1/JNK pathway and IL-6 blockade were used to examine HCC tumor load induced by preS1 deletions. ResultsPreS1Del variant selectively activates the IRE1 pathway, mainly via enhanced colocalization between the ER and HBsAg in infected hepatocytes. This leads to enhanced HBV replication and the production of tumor-promoting inflammatory cytokines and the genes IL-6 and COX-2 via the IRE1-JNK signaling pathway. Furthermore, in vivo data showed that the activation of IRE1-JNK signaling consequently leads to lipid accumulation and apoptosis within 21Del-HBV-infected-hepatocytes, collectively driving severe tumorigenesis in the liver. Notably, several inhibitors of the IRE1/JNK pathway dramatically inhibit HBV replication and inflammation induced by 21Del but not by the wild type in infected hepatocytes. Furthermore, IL-6 blockade significantly reduced HCC tumor load induced by 21Del HBV. ConclusionsPreS1Del leads to enhanced HBV replication and HCC development through IRE1-JNK-IL6/COX2-mediated hepatocyte proliferation and liver inflammation. Inhibitors interfering with the IRE1-JNK-IL6 pathway could selectively inhibit HBV replication and inflammation in preS1Dels, suggesting their potential for the treatment of CHB patients infected with preS1-deleted HBV variants. Impact and implicationsDeletion of 15 to 21 nucleotides at the preS1 start codon is common in chronic hepatitis B patients with HBV genotype C and is linked to HCC progression. However, the mechanisms underlying the distinct phenotype of this variant remain largely unknown. We found that the preS1Del variants selectively activates the IRE1 pathway, primarily through enhanced IRE1-JNK-IL6 signaling. Inhibition of either the IRE1-JNK pathway or IL-6 reduces HBV replication and tumor load in in vivo HCC models. This study enhances our understanding of the mechanisms of liver disease progression caused by 5’ preS1Del variants and provides new insights into treatment strategies for patients infected with these variants. We believe our findings will resonate with a diverse audience, including patients and their physicians, the medical community, academia, the life sciences sector, and the general public.