2. Academic Validation
  3. Hepatitis B virus core protein promotes liver cancer progression by stabilizing CANX and suppressing IRF7 transcription

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

  • Acta Pharmacol Sin. 2025 Jun 13. doi: 10.1038/s41401-025-01586-8.
Hong-Juan You # 1,  Huan-Yang Zhang # 1,  Yu-Jie Zhong 1,  Ru-Yu Liu 2,  Lu Yang 1,  Rong Jiang 1,  Yu-Xin Wang 1,  En-Si Bao 1,  Xiang-Ye Liu 1,  Chen Li 1,  Xiu-Cheng Pan 3,  Xu-Feng Huang 1 4,  Kui-Yang Zheng 1 5,  Ren-Xian Tang 6 7,  Fan-Yun Kong 8
Affiliations

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.
  • 2 Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
  • 3 Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China.
  • 4 Illawarra Health and Medical Research Institute (IHMRI) and School of Medical, Indigenous and Health Sciences, University of Wollongong, Wollongong, NSW, Australia.
  • 5 National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, 221004, China.
  • 6 Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, 221004, China. tangrenxian-t@163.com.
  • 7 National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, 221004, China. tangrenxian-t@163.com.
  • 8 Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, 221004, China. kong.fanyun@163.com.
  • # Contributed equally.
PMID: 40514420 DOI: 10.1038/s41401-025-01586-8
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.

Keywords

CANX; CBL; HDAC3; Hepatitis B virus core protein; IRF7; liver cancer.

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