Niemann-Pick type C1 protein regulates epidermal growth factor receptor stability in hepatic cells and facilitates the early steps of Hepatitis B virus infection

<jats:sec> <jats:title>Background</jats:title> <jats:p>Chronic Hepatitis B virus (HBV) infection affects more than 250 million individuals worldwide, causing up to 1 million deaths yearly. Despite the significant disease burden, no curative therapy against HBV is currently available. Accumulating evidence indicate a strong and complex relationship between HBV and the host-cell lipid metabolism. HBV hijacks host lipoprotein transport pathways to gain access to hepatocytes and uses cellular cholesterol and sphingolipids for morphogenesis, while viral replication induces diverse and profound alterations of the hepatic lipid metabolism driving disease progression and tumorigenesis. As a key regulator of the cellular cholesterol homeostasis, the Niemann-Pick C1 (NPC1) protein has increasingly been associated with a wide range of pathologies, including viral infections.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>In this study, we investigated HBV entry, replication, viral particle envelopment and secretion in cells depleted of NPC1 expression or treated with various FDA-approved NPC1 inhibitors.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Our work revealed that both genetic depletion and pharmacological inhibition of NPC1 impaired the early steps of HBV infection while significantly reducing the level and intracellular distribution of the HBV co-receptor, the Epidermal Growth Factor Receptor (EGFR).</jats:p> </jats:sec> <jats:sec> <jats:title>Discussion</jats:title> <jats:p>Mechanistically, NPC1 inhibition promoted EGFR depletion from the plasma membrane by enhancing the endocytic trafficking and degradation of the receptor within the endosomal-lysosomal compartment of hepatic cells. Considering the crucial roles of EGFR in tumorigenesis across multiple cancer types, our study promotes the newly identified NPC1-EGFR regulatory axis as a promising dual target for the development of antiviral and anticancer therapies.</jats:p> </jats:sec>