Netrin-1 Found to Block Hepatitis B Virus Entry into Liver Cells

Hepatitis B virus (HBV) infects more than 250 million people worldwide and remains a leading cause of chronic liver disease and liver cancer. While existing antiviral drugs suppress viral replication, they cannot fully clear the virus, emphasizing the need for approaches that stop HBV from entering liver cells in the first place.

Previous research identified Netrin‑1, a secreted laminin‑related protein, as a key factor that disrupts multiple stages of HBV entry. Known for its established roles in neural guidance and immune regulation, Netrin‑1 is now recognized for its antiviral function. Through a screening method focused on endothelial lipase (LIPG)—a host protein that facilitates HBV attachment to hepatocytes—a team from Kanazawa University determined that Netrin‑1 is an LIPG‑interacting protein with strong anti‑HBV activity.

Synthetic peptides derived from segments of Netrin‑1 displayed potent inhibition of the virus. In experiments using primary human hepatocytes, Netrin‑1 effectively blocked HBV infection. Likewise, in HepG2‑NTCP‑YFP cells, it suppressed both viral attachment and internalization, showing its capacity to interfere at multiple points during viral entry.

Further analysis revealed the mechanism behind this inhibition. Netrin‑1 binds to LIPG through heparin‑binding regions in its V and C domains, preventing LIPG from attaching to heparan sulfate proteoglycans (HSPGs) and from associating with HBV. In addition, Netrin‑1 interacts with the extracellular region of the epidermal growth factor receptor (EGFR), disrupting formation of the NTCP‑EGFR complex. This action blocks EGFR dimerization and phosphorylation, hindering a key pathway for HBV entry that operates independently of HSPGs.

In vivo studies using humanized hepatocyte chimeric mice confirmed that recombinant Netrin‑1 significantly reduced HBV infection. Together, these results identify Netrin‑1 as a multifunctional host factor that interferes with several steps of viral entry, presenting a promising target for new therapeutic strategies against HBV.

Masao Honda, corresponding author of the study published in PLOS Pathogens, notes, “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.”