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

Chen Su, Zhibin Liao, Jie Mo, Furong Liu, Weijian Wang, Haoquan Zhang, Hongwei Zhang, Yachong Liu, Yonglong Pan, He Zhu, Xiaoping Chen, Zhanguo Zhang (), Peng Zhu () and Bixiang Zhang ()
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Chen Su: 1095 Jiefang Avenue
Zhibin Liao: 1095 Jiefang Avenue
Jie Mo: 1095 Jiefang Avenue
Furong Liu: 1095 Jiefang Avenue
Weijian Wang: 1095 Jiefang Avenue
Haoquan Zhang: 1095 Jiefang Avenue
Hongwei Zhang: 1095 Jiefang Avenue
Yachong Liu: 1095 Jiefang Avenue
Yonglong Pan: 1095 Jiefang Avenue
He Zhu: 1095 Jiefang Avenue
Xiaoping Chen: 1095 Jiefang Avenue
Zhanguo Zhang: 1095 Jiefang Avenue
Peng Zhu: 1095 Jiefang Avenue
Bixiang Zhang: 1095 Jiefang Avenue

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64079-6

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