ArticleJHEP reports : innovation in hepatology2024
Hepatitis B surface antigen expression impairs endoplasmic reticulum stress-related autophagic flux by decreasing LAMP2.
Article in JHEP reports : innovation in hepatology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 11 citations in OpenAlex.
- Spatial-quantitative profiling of intrahepatic HBsAg heterogeneity and clustered distribution in chronic HBV infection.JHEP reports : innovation in hepatology · 2026Article
- Protein quality control and antigen presentation in the development of hepatitis B-related hepatocellular carcinoma.Frontiers in pharmacology · 2026Review
- The "viral-metabolic" interaction mechanisms and management challenges in chronic hepatitis B combined with metabolic dysfunction-associated fatty liver disease: from clinical evidence to an integrated multidisciplinary framework.Frontiers in immunology · 2026Review
- Hepatitis B virus, alcohol, and liver cancer.Frontiers in oncology · 2026Review
- Autophagy Dysregulation in Crohn's Disease and Colorectal Cancer-An Analysis ofCurrent issues in molecular biology · 2025Article
- Dual defects in HBsAg antigenicity and secretion caused by the C138R mutation in the S gene trigger occult hepatitis B virus infection.Journal of translational medicine · 2025Article
- The impact of single-nucleotide variants of hepatitis B virus and antiviral on liver cancer in gray zone patients.Journal of biomedical science · 2025Article
- HBV core protein enhances WDR46 stabilization to upregulate NUSAP1 and promote HCC progression.Hepatology communications · 2025Article
- Engineered extracellular vesicles as nanosponges for lysosomal degradation of PCSK9.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- The endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 3 attenuates the unfolded protein response and has pro-survival and pro-viral roles in hepatoma cells and hepatocellular carcinoma patients.Journal of biomedical science · 2025Article
- Current status and challenges of therapeutic targets, novel drugs and delivery systems for hepatitis B: how far to our goal?Frontiers in cellular and infection microbiology · 2025Review
- Hepatitis B virus entry, assembly, and egress.Microbiology and molecular biology reviews : MMBR · 2024Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Background & Aims: Hepatitis B surface antigen (HBsAg) drives hepatocarcinogenesis. Factors and mechanisms involved in this progression remain poorly defined, hindering the development of effective therapeutic strategies. Therefore, the mechanisms involved in the HBsAg-induced transformation of normal liver into hepatocellular carcinoma (HCC) were investigated. Methods: Hemizygous Tg(Alb1HBV)44Bri/J mice were examined for HBsAg-induced carcinogenic events. Gene set-enrichment analysis identified significant signatures in HBsAg-transgenic mice that correlated with endoplasmic reticulum (ER) stress, unfolded protein response, autophagy and proliferation. These events were investigated by western blotting, immunohistochemical and immunocytochemical staining in 2-, 8- and 12-month-old HBsAg-transgenic mice. The results were verified in HBsAg-overexpressing Hepa1-6 cells and validated in human HBV-related HCC samples. Results: Increased BiP expression in HBsAg-transgenic mice indicated induction of the unfolded protein response. In addition, early-phase autophagy was enhanced (increased BECN1 and LC3B) and late-phase autophagy blocked (increased p62) in HBsAg-transgenic mice. Finally, HBsAg altered lysosomal acidification via ATF4- and ATF6-mediated downregulation of lysosome-associated membrane protein 2 (LAMP2) expression. In patients, HBV-related HCC and adjacent tissues showed increased BiP, p62 and downregulated LAMP2 compared to uninfected controls. Conclusions: These data showed that HBsAg directly induces ER stress, impairs autophagy and promotes proliferation, thereby driving hepatocarcinogenesis. In addition, this study expanded the understanding of HBsAg-mediated intracellular events in carcinogenesis. Impact and implications: Factors and mechanisms involved in hepatocarcinogenesis driven by hepatitis B surface antigen (HBsAg) are poorly defined, hindering the development of effective therapeutic strategies. This study showed that HBsAg-induced endoplasmic reticulum stress suppressed LAMP2, thereby mediating autophagic injury. The present data suggest that restoring LAMP2 function in chronic HBV infection may have both antiviral and anti-cancer effects. This study has provided insights into the role of HBsAg-mediated intracellular events in carcinogenesis and thereby has relevance for future drug development.
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