H4C1 (H4 clustered histone 1) is a histone protein with structural roles in chr6 organization and nucleosome assembly [GO Annotations]. While its canonical function involves DNA binding and chr6 organization [GO Annotations], emerging evidence identifies H4C1 as a biomarker in disease pathophysiology. In NK cell immunotherapy, H4C1 was identified as a critical differentially regulated gene following amoxicillin treatment, with upregulation correlating with enhanced NK cell cytotoxicity and tumor-killing effects in breast cancer models 1. In metabolic liver disease, H4C1 protein levels are elevated in plasma extracellular vesicles from patients with advanced steatosis (S3) compared to mild steatosis (S1), suggesting its involvement in disease progression 2. Additionally, H4C1 demonstrates diagnostic utility in pediatric bacterial meningitis, where it forms part of a biomarker panel (ELANE and H4C1) achieving superior diagnostic accuracy (AUC = 0.967) for distinguishing infected from non-infected patients 3. These findings suggest H4C1 functions beyond structural chr6 roles, serving as a potential biomarker for immune activation, metabolic dysfunction, and infectious disease pathophysiology.