Liver mechanosignaling as a natural anti-hepatitis B virus mechanism

Jianyu Ye, Fahong Li, Ting Hua, Kewei Ma, Jinyu Wang, Zixin Zhao, Zhongning Yang, Chen Luo, Ruohan Jia, Yaming Li, Menghan Hao, Jian Wu, Mengji Lu, Zhenghong Yuan (), Jiming Zhang () and Jieliang Chen ()
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Jianyu Ye: Shanghai Medical College Fudan University
Fahong Li: Shanghai Medical College Fudan University
Ting Hua: Shanghai Medical College Fudan University
Kewei Ma: Shanghai Medical College Fudan University
Jinyu Wang: Shanghai Medical College Fudan University
Zixin Zhao: Shanghai Medical College Fudan University
Zhongning Yang: Shanghai Medical College Fudan University
Chen Luo: Shanghai Medical College Fudan University
Ruohan Jia: Shanghai Medical College Fudan University
Yaming Li: Shanghai Medical College Fudan University
Menghan Hao: Shanghai Medical College Fudan University
Jian Wu: Shanghai Medical College Fudan University
Mengji Lu: University of Duisburg-Essen
Zhenghong Yuan: Shanghai Medical College Fudan University
Jiming Zhang: Shanghai Medical College Fudan University
Jieliang Chen: Shanghai Medical College Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The mechanisms underlying the natural control of hepatitis B virus (HBV) infection have long been an intriguing question. Given the wide physiological range of liver stiffness and the growing attention to the role of mechanical microenvironment in homeostasis and diseases, we investigated how physical matrix cues impact HBV replication. High matrix stiffness significantly inhibited HBV replication and activated YAP in primary hepatocyte culture system, a key molecule in mechanosignaling. YAP activation notably suppressed HBV transcription and antigen expression. Several YAP-induced genes exhibited strong anti-HBV effects. Single-cell analysis of liver tissue from male individuals with active HBV replication revealed a strong significant negative correlation between YAP signature activation and HBV transcript levels. Intraperitoneal administration of YAP small molecule agonist potently controls HBV in male mouse models. These findings unveil a mechanism that involves the mechanical environment of hepatocytes and YAP to clear hepatotropic viral infection in the liver, providing new perspectives for HBV cure studies and antiviral development.

Date: 2024
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DOI: 10.1038/s41467-024-52718-3

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