DEFA1 (defensin alpha 1) encodes human neutrophil peptide 1 (HNP-1), a key antimicrobial component of innate immunity. This α-defensin functions through multiple mechanisms: it directly kills bacteria by disrupting cell wall synthesis via interaction with lipid II, inhibits viral infections including adenovirus through capsid-mediated mechanisms, and promotes immune activation in dendritic cells. DEFA1 displays significant copy number variation (4-11 gene copies per diploid genome), which substantially modulates disease outcomes 1. In infectious contexts, elevated DEFA1 expression correlates with tuberculosis pathology and serves as a biomarker for Crohn's disease prediction up to 16 years before clinical onset 23. However, paradoxically, high DEFA1 copy number increases sepsis severity through endothelial cell pyroptosis via P2X7/NLRP3 inflammasome activation 4. Beyond infection, DEFA1 is upregulated in dental caries lesions and promotes oral squamous cell carcinoma invasion through monocyte-derived signaling via JNK/NF-κB pathways 56. DEFA1 expression is regulated by ATF4 in intestinal epithelial cells; its restoration alleviates inflammatory bowel disease severity in mice 7. These findings highlight DEFA1's context-dependent roles: protective against pathogens but potentially harmful during systemic inflammation and in tumor microenvironments.