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Hepatitis B virus promotes liver cancer by modulating the immune response to environmental carcinogens

Author

Listed:
  • Mei Huang

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    University of Science and Technology of China)

  • Dongyao Wang

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    University of Science and Technology of China)

  • Jiao Huang

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • An-Na Bae

    (Keimyung University)

  • Yun Xia

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Xutu Zhao

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Mahsa Mortaja

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Marjan Azin

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Michael R. Collier

    (Massachusetts General Hospital and Harvard Medical School)

  • Yevgeniy R. Semenov

    (Massachusetts General Hospital and Harvard Medical School
    Harvard Medical School)

  • Jong Ho Park

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    Keimyung University)

  • Shadmehr Demehri

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

Abstract

Hepatitis B virus (HBV) infection is associated with hepatitis and hepatocellular carcinoma (HCC). Considering that most HBV-infected individuals remain asymptomatic, the mechanism linking HBV to hepatitis and HCC remains uncertain. Herein, we demonstrate that HBV alone does not cause liver inflammation or cancer. Instead, HBV alters the chronic inflammation induced by chemical carcinogens to promote liver carcinogenesis. Long-term HBV genome expression in mouse liver increases liver inflammation and cancer propensity caused by a carcinogen, diethylnitrosamine (DEN). HBV plus DEN-activated interleukin-33 (IL-33)/regulatory T cell axis is required for liver carcinogenesis. Pitavastatin, an IL-33 inhibitor, suppresses HBV plus DEN-induced liver cancer. IL-33 is markedly elevated in HBV+ hepatitis patients, and pitavastatin use significantly correlates with reduced risk of hepatitis and its associated HCC in patients. Collectively, our findings reveal that environmental carcinogens are the link between HBV and HCC risk, creating a window of opportunity for cancer prevention in HBV carriers.

Suggested Citation

  • Mei Huang & Dongyao Wang & Jiao Huang & An-Na Bae & Yun Xia & Xutu Zhao & Mahsa Mortaja & Marjan Azin & Michael R. Collier & Yevgeniy R. Semenov & Jong Ho Park & Shadmehr Demehri, 2025. "Hepatitis B virus promotes liver cancer by modulating the immune response to environmental carcinogens," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60894-z
    DOI: 10.1038/s41467-025-60894-z
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    References listed on IDEAS

    as
    1. Joyce LaMori & Xue Feng & Christopher D Pericone & Marco Mesa-Frias & Obiageli Sogbetun & Andrzej Kulczycki, 2022. "Hepatitis vaccination adherence and completion rates and factors associated with low compliance: A claims-based analysis of U.S. adults," PLOS ONE, Public Library of Science, vol. 17(2), pages 1-19, February.
    2. Lu Zong & Hui Peng & Cheng Sun & Fenglei Li & Meijuan Zheng & Yongyan Chen & Haiming Wei & Rui Sun & Zhigang Tian, 2019. "Breakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    3. Lei Xu & Chuan Wei & Ying Chen & Yue Wu & Xiaoli Shou & Wenjie Chen & Di Lu & Haoran Sun & Wei Li & Beibei Yu & Xiaowei Wang & Xiaojun Zhang & Yanxiong Yu & Zhigang Lei & Rui Tang & Jifeng Zhu & Yalin, 2022. "IL-33 induces thymic involution-associated naive T cell aging and impairs host control of severe infection," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
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