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

作者：Su Chen, Zhibin Liao, Jie Mo, Furong Liu, Weijian Wang, Haoquan Zhang, Hongwei Zhang, Yachong Liu, Yonglong Pan, He Zhu, Xiaoping Chen, Zhanguo Zhang, Peng Zhu, Bixiang Zhang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64079-6 · 被引用次数：3 · 研究领域：Ubiquitin and proteasome pathways、Protein Degradation and Inhibitors、Endoplasmic Reticulum Stress and Disease

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. VRK Serine/Threonine Kinase 2 (VRK2) has shown to play a significant role in apoptosis, cell growth, and immune response. Here the authors report that VRK2 is a key regulator of hepatocellular...