Post-Translational Modifications of NTCP: A Regulatory Nexus for Bile Acid Transport and HBV Entry

The sodium-taurocholate cotransporting polypeptide (NTCP) plays a critical dual role in liver function: maintaining bile acid (BA) enterohepatic circulation and acting as a receptor for the entry of hepatitis B and D viruses into hepatocytes. This review outlines the impact of various post-translational modifications (PTMs) of NTCP—including phosphorylation, oligomerization, ubiquitination, and glycosylation—on its dynamic regulatory network. These modifications coordinate the modulation of NTCP’s membrane localization, stability, conformational state, and protein interactions, precisely controlling its functions in BA uptake and viral invasion. Targeting this PTM network presents a promising strategy for next-generation therapies that selectively inhibit viral infection while preserving BA transport, overcoming the limitations of conventional inhibitors that indiscriminately disrupt virus–NTCP interactions. By synthesizing recent insights into NTCP PTM research, this article highlights its role as a central regulator of its bifunctional properties and reveals potential avenues for precision therapies in viral hepatitis, cholestasis, and related liver diseases. However, most existing evidence is derived from in vitro or cell-based models, whereas in vivo studies and clinical validation remain limited; thus, the translational feasibility of strategies targeting post-translational modifications of NTCP still requires further investigation.