NAP1L3 (nucleosome assembly protein 1-like 3) is a histone chaperone located on the X chromosome X plays critical roles in cellular differentiation and chrX regulation. The protein shares 46% identity with NAP1L and contains conserved C-terminal motifs characteristic of nucleosome assembly proteins, with strong expression in adult brain tissue 1. NAP1L3 is essential for hematopoietic stem cell (HSC) maintenance and differentiation, with high expression restricted to HSCs in mice 2. Loss of NAP1L3 function reduces HSC numbers and reconstituting activities, causes G0 cell cycle arrest, and dysregulates cell cycle genes including E2F and MYC targets, while upregulating HOXA3 and HOXA5 genes 2. In cancer contexts, NAP1L3 promotes cisplatin resistance in ovarian cancer by activating the TGF-β pathway and increasing SMAD2/SMAD3 phosphorylation and nuclear translocation 3. NAP1L3 also contributes to hepatocellular carcinoma progression through the miR-498/NAP1L3 axis 4 and enhances breast cancer metastatic efficiency 5. Additionally, NAP1L3 variants have been identified in men with non-obstructive azoospermia, representing the first clinical description of this gene in male infertility 6.