VRK2 is a serine/threonine kinase that regulates multiple cellular processes including p53 stabilization, apoptosis, and immune signaling. The protein phosphorylates p53 at threonine-18 and histone H3, reducing p53 ubiquitination by MDM2 while promoting its acetylation, thereby increasing p53 stability and transcriptional activity. VRK2 exists as two isoforms with distinct subcellular localizations: the main isoform (VRK2A) anchors to the endoplasmic reticulum, mitochondria, and nuclear envelope, while an alternative splice variant (VRK2B) can translocate to the nucleus when VRK1 levels are low. In cancer, VRK2 overexpression contributes to disease progression through multiple mechanisms. In hepatocellular carcinoma, VRK2 stabilizes the MYC oncoprotein through phosphorylation, blocking its proteasomal degradation and amplifying immune checkpoint ligand expression; VRK2 kinase inhibition synergizes with anti-PD-1 immunotherapy 1. In colorectal cancer, VRK2 promotes cell proliferation via the E2F pathway and confers resistance to 5-FU chemotherapy 2. Conversely, in glioblastoma with VRK2 promoter methylation, VRK1 becomes essential for survival, making VRK1 inhibition a synthetic-lethal therapeutic strategy 34. Genetically, VRK2 variants associate with multiple psychiatric and neurological disorders in European and Han Chinese populations. The SNP rs1518395 shows genome-wide significant association with schizophrenia and major depressive disorder 5, with reduced VRK2 mRNA levels specific to schizophrenia spectrum disorders 6. Rare variants link to epilepsy, bipolar disorder, autism, and sleep-duration variation 78.