TSPYL5 (TSPY like 5) is a multifunctional protein that serves as both a histone chaperone and a critical regulator of p53 signaling. As a histone chaperone, TSPYL5 preferentially binds histone H3/H4 complexes through its C-terminal NAP-like domain and facilitates nucleosome assembly and histone deposition onto DNA 1. The protein functions as a dimer that can bind either two H3/H4 dimers or a single tetramer, establishing it as a member of the NAP histone chaperone family 1. In p53 regulation, TSPYL5 promotes p53 cytoplasmic sequestration through multiple mechanisms: it enhances G3BP1 phosphorylation and nuclear membrane translocation, forming RanBP2-G3BP1-p53 complexes that accelerate p53 sumoylation and nuclear export 2. Additionally, TSPYL5 suppresses p53 protein levels and promotes its ubiquitination independently of MDM2 3. TSPYL5 also modulates the AKT/PTEN pathway, where AKT phosphorylates TSPYL5 at threonine-120, leading to its nuclear translocation and transcriptional suppression of PTEN, creating a positive feedback loop 45. This regulation influences cell proliferation, radiation resistance, and cancer stem cell characteristics 45. Clinically, TSPYL5 hypermethylation occurs in hepatocellular carcinoma and breast cancer, suggesting tumor suppressor functions, while its overexpression promotes endothelial cell function and angiogenesis 673.