H2BC21 (H2B clustered histone 21) is a histone protein with dual roles in chr1 structure and innate immunity. As a structural component of chr1, it participates in nucleosome assembly and DNA binding, maintaining normal chromosome 1 1. Beyond its canonical histone function, H2BC21 exhibits broad antimicrobial activity, contributing to the antimicrobial barrier of the colonic epithelium and bactericidal activity of amniotic fluid through antimicrobial humoral immune responses and defense against Gram-positive bacteria. H2BC21 has emerged as a biomarker across multiple disease states. It is upregulated as a hub gene in the bidirectional relationship between Type 2 Diabetes Mellitus and periodontitis, suggesting a role in inflammatory disease pathogenesis 2. In Parkinson's disease, H2BC21 expression changes in both substantia nigra and peripheral blood mononuclear cells associate with disease status, making it a candidate diagnostic biomarker 3. Additionally, H2BC21 functions as a glucose metabolism-related prognostic gene in colon adenocarcinoma, with elevated expression correlating with poorer survival outcomes 4. In depression and cognitive impairment comorbidity, H2BC21 was identified as a hub gene in protein-protein interaction networks linking these conditions 5. These findings suggest H2BC21 participates in both fundamental chr1 biology and broader immune and metabolic responses relevant to multiple pathological states.