Wild‐Type and rtA181T/sW172* Mutant Strains of Hepatitis B Virus Drive Hepatocarcinogenesis via Distinct GRP78‐Mediated ER Stress Pathways

ABSTRACT Glucose‐regulated protein 78 kDa (GRP78), a key marker of endoplasmic reticulum stress (ERS), is upregulated in hepatocellular carcinoma (HCC) tissues, but its role in hepatitis B virus (HBV)‐induced tumorigenesis remains unclear. This study aimed to investigate the contribution of GRP78 to HBV‐associated tumor development and explore the ERS pathways involved. The results showed that increased GRP78 expression in patients with HBV‐related HCC was associated with a poor prognosis within the first 2 years following diagnosis. Furthermore, using wild‐type HBV strain and the oncogenic HBV rtA181T/sW172* mutant, this study demonstrated that the HBV‐induced GRP78 expression correlated with elevated reactive oxygen species (ROS) levels. Moreover, GRP78 expression enhanced hepatocyte proliferation and resistance to apoptosis. In wild‐type HBV‐infected hepatocytes, GRP78 suppressed apoptosis by inhibiting the PERK/p38 pathway. In contrast, the HBV rtA181T/sW172* mutation led to increased GRP78 expression and inhibition of cell apoptosis through activation of the IRE‐1α/XBP1/BCL‐2 pathway. In conclusion, GRP78 plays a pivotal role in HBV‐induced hepatocarcinogenesis by modulating distinct ERS pathways. Targeting these pathways may aid in the therapeutic management of HBV‐associated hepatocarcinogenesis.