2. Academic Validation
  3. VRK2 targeting potentiates anti-PD-1 immunotherapy in hepatocellular carcinoma through MYC destabilization

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

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. zhanguo_tjh@hust.edu.cn.
  • 7 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China. zhanguo_tjh@hust.edu.cn.
  • 8 Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei, People's Republic of China. zhanguo_tjh@hust.edu.cn.
  • 9 Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, Hubei, People's Republic of China. zhanguo_tjh@hust.edu.cn.
  • 10 Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, People's Republic of China. zhanguo_tjh@hust.edu.cn.
  • 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. zhupeng@tjh.tjmu.edu.cn.
  • 12 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China. zhupeng@tjh.tjmu.edu.cn.
  • 13 Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei, People's Republic of China. zhupeng@tjh.tjmu.edu.cn.
  • 14 Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, Hubei, People's Republic of China. zhupeng@tjh.tjmu.edu.cn.
  • 15 Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, People's Republic of China. zhupeng@tjh.tjmu.edu.cn.
  • 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. bixiangzhang@hust.edu.cn.
  • 17 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, People's Republic of China. bixiangzhang@hust.edu.cn.
  • 18 Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei, People's Republic of China. bixiangzhang@hust.edu.cn.
  • 19 Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, Hubei, People's Republic of China. bixiangzhang@hust.edu.cn.
  • 20 Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, People's Republic of China. bixiangzhang@hust.edu.cn.
  • # 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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