VRK2 targeting potentiates anti-PD-1 immunotherapy in hepatocellular carcinoma through MYC destabilization

  • Nat Commun. 2025 Oct 10;16(1):9027. doi: 10.1038/s41467-025-64079-6.
Chen Su  #  1  2 ,  Zhibin Liao  #  1  2 ,  Jie Mo  #  1  2 ,  Furong Liu  #  1  2 ,  Weijian Wang  1  2 ,  Haoquan Zhang  1  2 ,  Hongwei Zhang  1  2 ,  Yachong Liu  1  2 ,  Yonglong Pan  1  2 ,  He Zhu  1  2 ,  Xiaoping Chen  1  2  3  4  5 ,  Zhanguo Zhang  6  7  8  9  10 ,  Peng Zhu  11  12  13  14  15 ,  Bixiang Zhang  16  17  18  19  20
Affiliations
  • 1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, Hubei, People's Republic of China.
  • 2. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China.
  • 3. Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei, People's Republic of China.
  • 4. Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, Hubei, People's Republic of China.
  • 5. Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, People's Republic of China.
  • 6. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, Hubei, People's Republic of China. [email protected].
  • 7. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China. [email protected].
  • 8. Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei, People's Republic of China. [email protected].
  • 9. Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, Hubei, People's Republic of China. [email protected].
  • 10. Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, People's Republic of China. [email protected].
  • 11. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, Hubei, People's Republic of China. [email protected].
  • 12. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China. [email protected].
  • 13. Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei, People's Republic of China. [email protected].
  • 14. Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, Hubei, People's Republic of China. [email protected].
  • 15. Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, People's Republic of China. [email protected].
  • 16. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, Hubei, People's Republic of China. [email protected].
  • 17. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China. [email protected].
  • 18. Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei, People's Republic of China. [email protected].
  • 19. Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, Hubei, People's Republic of China. [email protected].
  • 20. Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 41073389 DOI: 10.1038/s41467-025-64079-6
Abstract

Dysregulation of MYC proto-oncogene, bHLH transcription factor (MYC) represents a common yet mechanistically unresolved driver of hepatocellular carcinoma (HCC). While MYC remains an elusive therapeutic target, developing strategies to promote its degradation emerges as a promising alternative approach. Here we show that vaccinia-related kinase 2 (VRK2) functions as a direct MYC-interacting kinase that stabilizes the oncoprotein through phosphorylation at Serine (Ser)281/293. This phosphorylation enables VRK2 to compete with the Skp1-Cullin-F-box protein complex containing FBXO24 (SCF-FBXO24) E3 Ligase, thereby blocking MYC polyubiquitination and proteasomal degradation. The stabilized MYC-VRK2 complex amplifies transcriptional activation of protumorigenic programs, including the immune checkpoint programmed cell death ligand 1 (PD-L1) and VRK2 itself, establishing a self-reinforcing oncogenic circuit. Therapeutic inhibition of VRK2 in HCC models reduces MYC protein levels, suppresses tumor progression, and synergizes with anti- programmed cell death-1 (PD-1) immunotherapy. Our results reveal VRK2-mediated stabilization of MYC as a critical nexus linking hepatocarcinogenesis to immune evasion, proposing VRK2 kinase inhibition as a mechanism-based therapeutic strategy for MYC-driven HCC.

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