VPS72 (vacuolar protein sorting 72 homolog) is a histone chaperone that specifically deposits the histone variant H2A.Z into nucleosomes as a component of the SRCAP chr1-remodeling complex 1. This ATP-dependent histone exchange regulates transcription of selected genes through chr1 remodeling [UniProt annotation]. Beyond its canonical chr1 function, VPS72 plays a critical role in nuclear reassembly following mitosis, with VPS72 depletion extending telophase and producing malformed nuclei 1. VPS72 is significantly amplified and overexpressed in hepatocellular carcinoma (HCC), where it functions as an oncogenic driver 2. Multiple mechanistic pathways contribute to HCC progression: VPS72 interacts with ACTL6A and MYC to enhance transcription of oncogenic targets 3; promotes de novo lipogenesis through ATF3-mediated repression and mTORC1 activation 4; and activates PI3K/AKT signaling via KAT5 binding 5. Additionally, VPS72 overexpression correlates with reduced CD4+ T cell infiltration and increased M0 macrophage recruitment, suggesting immune suppression 6. VPS72 copy number gains associate with poor prognosis and serve as an independent prognostic factor in HCC 47. Elevated VPS72 expression also promotes prostate cancer progression through NF-κB pathway activation 8. These findings establish VPS72 as a therapeutic target and diagnostic/prognostic biomarker for multiple malignancies.