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Hepatitis B virus core protein promotes liver cancer progression by stabilizing CANX and suppressing IRF7 transcription

Acta Pharmacologica Sinica volume 46, pages 3036–3052 (2025)Cite this article

Abstract

Hepatitis B virus (HBV) infection is a vital risk factor for the development of liver cancer. HBV core protein (HBC) contributes to the tumorigenesis induced by the virus. How HBC regulates liver cancer progress has not been well elucidated yet. Calnexin (CANX) is a molecular chaperone that benefits the folding and quality control of various proteins. Overexpression of CANX is implicated in the development of various type of cancers. In this study we investigated the clinical association and biological effects of CANX in liver cancer, and the underlying mechanisms. We showed that the expression of CANX was significantly increased in HBV-associated liver cancer, and its upregulation was relevant to the unfavorable survival of patients with the tumor. We demonstrated that CANX facilitated the growth and migration ability of HBC-positive tumor cells in vitro and in vivo. We identified CBL as a novel E3 ligase of CANX with the function of inducing the ubiquitination of CANX to promote its degradation. HBC increased the stabilization CANX protein by disrupting its interaction with CBL. We revealed that IRF7, an interferon regulatory factor, was an important downstream target of CANX. CANX inhibited IRF7 transcription to promote the proliferation and migration of HBC-positive tumor cells in vitro and in vivo. HDAC3, a histone deacetylase with the capacity to interact with IRF7 promoter, participated in CANX-mediated inhibition on IRF7 gene transcription. HBC enhanced the interaction between CANX and HDAC3, facilitated the recruitment of HDAC3 to IRF7 promoter, leading to the decrease of IRF7 transcription. Finally, we conducted a high-throughput virtual screening to screen potential CANX inhibitors in the APExBIO bioactive compound library. We showed that a candidate compound fluzoparib effectively suppressed HBC-positive liver cancer cells in vitro and in vivo. Overall, this study underscores the crucial role of CANX and its regulatory mechanisms in promoting HBC-mediated liver cancer progression and reveals the therapeutic potential of targeting CANX in HBV infection-caused liver cancer.

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Fig. 1: The expression of CANX is increased in liver cancer and it can be upregulated by HBC.
Fig. 2: The effect of CANX on cell proliferation and migration mediated by HBC in vitro and in vivo.
Fig. 3: HBC disrupted the interaction between CANX with CBL to stabilize CANX protein.
Fig. 4: CANX suppresses IRF7 transcription in HBC-positive liver cancer cells.
Fig. 5: The effect of IRF7 on cell proliferation and migration mediated by CANX in vitro and in vivo.
Fig. 6: The effect of HDAC3 on the expression of IRF7 mediated by CANX and HBC.
Fig. 7: The inhibitory effect of FZ on CANX to reduce cell proliferation and migration mediated by HBC in vitro and in vivo.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (82372245), the Natural Science Foundation of Jiangsu Province (BK20211347), the Natural Science Foundation of the Jiangsu Higher Education Institutions (21KJA310004), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the National Demonstration Center for Experimental Basic Medical Science Education (Xuzhou Medical University) Student Science and Technology Innovation Project (2024BMS27), and the Qing Lan Project of Jiangsu Province. Supplementary Fig. S2 was created by BioRender (https://biorender.com/).

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  1. These authors contributed equally: Hong-juan You, Huan-yang Zhang.

Authors and Affiliations

  1. Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, 221004, China

    Hong-juan You, Huan-yang Zhang, Yu-jie Zhong, Lu Yang, Rong Jiang, Yu-xin Wang, En-si Bao, Xiang-ye Liu, Chen Li, Xu-feng Huang, Kui-yang Zheng, Ren-xian Tang & Fan-yun Kong

  2. Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China

    Ru-yu Liu

  3. Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China

    Xiu-cheng Pan

  4. Illawarra Health and Medical Research Institute (IHMRI) and School of Medical, Indigenous and Health Sciences, University of Wollongong, Wollongong, NSW, Australia

    Xu-feng Huang

  5. National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, 221004, China

    Kui-yang Zheng & Ren-xian Tang

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Contributions

FYK, HYZ, and HJY conducted experiments and wrote the manuscript; YJZ, LY, RJ, YXW, CL, XYL, and ESB performed the experiments and the data analysis; XCP and RYL contribute to clinical sample collection and statistical analysis; XFH, KYZ, RXT, and FYK designed the research, supervised the project, and checked the data. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ren-xian Tang or Fan-yun Kong.

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You, Hj., Zhang, Hy., Zhong, Yj. et al. Hepatitis B virus core protein promotes liver cancer progression by stabilizing CANX and suppressing IRF7 transcription. Acta Pharmacol Sin 46, 3036–3052 (2025). https://doi.org/10.1038/s41401-025-01586-8

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