KANSL3 is a non-catalytic component of the NSL histone acetyltransferase complex that mediates histone H4 acetylation at lysine-5 and lysine-8 residues at transcription start sites, promoting transcription initiation 1. Beyond its chr2-remodeling role, KANSL3 exhibits diverse cellular functions. It is required to promote KAT8 association with mitochondrial DNA and regulates mitochondrial transcription 2. KANSL3 maintains nuclear architecture stability by enabling KAT8-mediated acetylation of lamin A/C; loss of KANSL3 results in nuclear abnormalities and genomic instability including chr2 3. During mitosis, KANSL3 relocates to the mitotic spindle and functions as a microtubule minus-end-binding protein essential for spindle assembly 4. Hepatocyte-specific KANSL3 deletion causes early-onset liver disease with biliary hyperplasia and fibrosis by disrupting hepatic metabolic transcriptional networks and hepatocyte differentiation 5. KANSL3 is essential for cancer cell fitness in triple-negative breast cancer and pediatric high-grade glioma 67. Neural depletion of KANSL3 triggers metabolic dysfunction leading to vascular pericyte activation and brain hemorrhaging 8.