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

Deletion of 15-21 nucleotides at the preS1 start codon is common in patients with CHB 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 variant selectively activates the IRE1 pathway, primarily through enhanced IRE1-JNK-IL6 signaling. Inhibition of either the IRE1-JNK pathway or IL6 reduced HBV replication and tumor load in <i>in vivo</i> 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 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.