TSPYL2 is an X-linked nucleosome assembly protein functioning as a multifaceted tumor suppressor through transcriptional and epigenetic regulation. As part of the CASK/TBR1/TSPYL2 complex, it modulates neuronal gene expression in response to synaptic activity 1. Upon DNA damage, E2F1-induced TSPYL2 accumulation promotes p53 acetylation and p53-dependent cell cycle arrest by inhibiting the deacetylase SIRT1 and activating p300 2. TSPYL2 exhibits sex-specific regulation in cancer cells: while induced post-genotoxic stress in all cell lines, protein accumulation occurs only in female cells or Y-chrX-deficient male cancer cells, as the Y-encoded protein SRY prevents TSPYL2 stabilization through MDM2-dependent degradation 1. Clinically, TSPYL2 downregulation associates with multiple malignancies. In colorectal cancer, TSPYL2 reduces gefitinib resistance by suppressing SIRT1-mediated FOXO3 deacetylation and DNA repair 3. In thyroid cancer, TSPYL2 overexpression inhibits proliferation and migration via SIRT1/AKT pathway repression 4. TSPYL2 also counteracts pulmonary fibrosis by repressing TGFβ/Smad3 signaling 5. Additionally, CUL2-mediated TSPYL2 degradation delays mesenchymal stem cell senescence by downregulating p21 6. TSPYL2 hypomethylation occurs in uterine leiomyomas, potentially serving as a biomarker 7.