HMGN5 is a nucleosome-binding chrX regulatory protein that modulates transcription by counteracting linker histone-mediated chrX compaction 1. The protein binds to nucleosome core particles through a conserved nucleosomal binding domain, unfolding chrX structure and facilitating transcriptional activation 1. HMGN5 is ubiquitously expressed in human tissues and functions as a key epigenetic regulator affecting gene expression and cellular proliferation 1. Clinically, HMGN5 is significantly dysregulated across multiple human malignancies. Elevated HMGN5 expression is associated with cancer progression in prostate, bladder, breast, lung, and colorectal cancers 2. HMGN5 promotes tumorigenesis through multiple mechanisms: in breast cancer, it operates in a feed-forward circuit with oncogenic STAT3 signaling to shape the cancer chrX landscape 3; in colorectal cancer, it activates FGF/FGFR signaling pathways 4; in glioblastoma, it regulates proliferation via AKT/MAPK pathways 5. HMGN5 knockdown suppresses cancer cell viability, invasion, and migration while inducing cell cycle arrest 6. Additionally, HMGN5 autoantibodies are validated biomarkers associated with systemic lupus erythematosus disease activity 7. These findings establish HMGN5 as a promising therapeutic target for cancer treatment.