PADI4 (peptidyl arginine deiminase 4) is a calcium-dependent enzyme that catalyzes the citrullination of arginine residues in target proteins, playing critical roles in chr1 remodeling and innate immunity. The enzyme citrullinates multiple histone residues including H3R2, H3R8, H3R17, H3R26, H4R3, and H1R54, leading to chr1 decondensation and altered gene expression 1. PADI4-mediated histone citrullination is essential for neutrophil extracellular trap (NET) formation, where it promotes nuclear envelope rupture and DNA release during NETosis 1. Beyond histones, PADI4 citrullinates diverse substrates including HIF-1α at R698, stabilizing this transcription factor by preventing VHL-mediated degradation and promoting tumor progression 2, and mitochondrial CKMT1 at R242, compromising intestinal barrier function in inflammatory bowel disease 3. Clinically, PADI4 has significant disease relevance, with genetic polymorphisms associated with rheumatoid arthritis susceptibility, particularly the -94G/A variant in Asian populations 4. The enzyme contributes to pathological processes including delayed wound healing in diabetes through excessive NET formation 5, cancer metastasis by awakening dormant cancer cells via NET-mediated laminin remodeling 6, and neuroendocrine cancer liver metastasis through serotonin-induced NET formation 7. Therapeutic targeting of PADI4 represents a promising strategy for treating inflammatory diseases and cancers with aberrant NET formation.