Intracellular Zn²⁺ levels regulate susceptibility to hepatitis B virus infection by modulating NTCP-mediated viral entry.

Authors

Yumi Itoh, Chiharu Morita, Cui Jinzi, Tatsuya Suzuki, Aiko Ono, Tomomi Hishinuma, Kento Fukano, Daisuke Okuzaki, Daisuke Motooka, Kei Miyakawa, Yasuyoshi Hatayama, Akihide Ryo, Mitsuyoshi Suzuki, Hajime Takei, Hiroshi Nittono, Tomokazu Tanaka, Koichi Watashi, Masamichi Muramatsu, Kohji Moriishi, Yoshiharu Matsuura, Toru Okamoto

Published in

Antiviral research. Pages 106542. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

Hepatitis B virus (HBV) infection remains a significant global health challenge and is a leading cause of chronic liver diseases, including cirrhosis and hepatocellular carcinoma. Although nucleos(t)ide analogs and interferon-based therapies suppress viral replication, they do not eliminate the viral reservoir, highlighting the need for novel therapeutic strategies. HBV utilizes the sodium taurocholate cotransporting polypeptide (NTCP) as a key receptor for hepatocyte entry; however, the underlying mechanisms governing this process remain incompletely understood. In this study, we demonstrate that intracellular Zn²⁺ levels, regulated by zinc transporter 1 (ZnT1), also known as solute carrier family 30 member 1 (SLC30A1), serve as critical modulators of HBV entry. Zinc supplementation significantly reduced both HBV and hepatitis D virus infection in NTCP-expressing hepatocytes without affecting post-entry replication steps. Knockout or knockdown of SLC30A1 led to intracellular Zn²⁺ accumulation and impaired HBV infection, effects reversed by re-expression of functional SLC30A1 or treatment with the Zn²⁺ chelator TPEN. Mechanistically, elevated Zn²⁺ levels disrupted NTCP-mediated HBV/HDV internalization and bile acid uptake, implicating Zn²⁺ in the regulation of receptor activity. RNA sequencing analysis further revealed transcriptional reprogramming of metabolic and bile acid-associated pathways in Zn²⁺-treated cells. Collectively, these findings reveal a role for intracellular zinc homeostasis in regulating HBV entry and implicate the SLC30A1-Zn2+-NTCP axis in this process.

PMID:
42810521
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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