Netrin-1 disrupts hepatitis B virus attachment and internalization, offering new treatment path

Netrin-1 blocks hepatitis B virus entry by preventing LIPG-mediated attachment to hepatocytes and suppressing EGFR-driven internalization. Credit: PLOS Pathogens (2025). DOI: 10.1371/journal.ppat.1013776

Hepatitis B virus (HBV) infects more than 250 million people worldwide and can lead to chronic liver disease and liver cancer. Current antiviral therapies suppress viral replication but do not eliminate the virus, highlighting the urgent need for new strategies to block HBV entry into liver cells.

Netrin-1, a secreted laminin-related protein, is increasingly recognized not only for its established functions in neural guidance and immune regulation but also for its potential roles in viral pathogenesis.

Discovery of Netrin-1’s antiviral properties

In previous studies, the researchers, affiliated with Kanazawa University, identified endothelial lipase (LIPG) as a host factor that facilitates hepatitis B virus attachment to hepatocytes via heparan sulfate proteoglycans (HSPGs) and/or the sodium taurocholate co-transporting polypeptide (NTCP).

Using LIPG-based screening, the team identified Netrin-1 as an LIPG-interacting protein. Synthetic peptides derived from Netrin-1 sequences exhibited potent anti-HBV activity. In primary human hepatocytes, Netrin-1 effectively inhibited HBV infection, and in HepG2-NTCP-YFP cells, it suppressed both viral attachment and internalization.

Mechanisms of Netrin-1 action

Mechanistically, studies revealed that Netrin-1 binds LIPG via heparin-binding motifs in its V and C domains, disrupting the interaction of LIPG to HSPGs and LIPG to HBV. Additionally, Netrin-1 interacts with the extracellular domain of epidermal growth factor receptor (EGFR), preventing NTCP-EGFR complex formation and inhibiting EGFR dimerization and phosphorylation, independently of HSPGs.

In vivo experiments using humanized hepatocyte chimeric mice demonstrated that recombinant Netrin-1 suppresses HBV infection. These findings establish Netrin-1 as a multifunctional host factor that interferes with multiple steps of HBV entry, highlighting its potential as a novel therapeutic strategy for HBV infection and chronic hepatitis B.

Professor Masao Honda from Kanazawa University, the corresponding author of the paper published in PLOS Pathogens, says, “Our study reveals a previously unrecognized role of Netrin-1 in blocking hepatitis B virus entry into hepatocytes by interfering with both viral attachment and internalization. We hope this work will inspire further research into multifunctional host factors that can be leveraged to combat viral infections.”

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