DEFA4 (defensin alpha 4) is a host-defense antimicrobial peptide belonging to the alpha-defensin family with primary activity against Gram-negative bacteria, including E. coli and E. aerogenes, and lesser activity against Gram-positive bacteria (S. aureus, B. cereus) and fungi (C. albicans) 1. The peptide functions through disruption of pathogen membrane integrity and exhibits antiviral properties, specifically protecting blood cells against HIV-1 infection by interacting with viral surface protein gp120 1. Additionally, DEFA4 inhibits Bacillus anthracis lethal factor enzymatic activity and suppresses corticosterone production, suggesting immunomodulatory roles 1. Clinically, DEFA4 emerges as a biomarker in multiple disease contexts. Reduced DEFA4 expression in intestinal epithelial cells correlates with inflammatory bowel disease severity, where ATF4-mediated regulation controls DEFA4 transcription 2. DEFA4 serves as a protective factor against periodontitis, with decreased expression associated with disease susceptibility 3. The gene functions as a diagnostic biomarker for lupus nephritis (AUC=0.843) and periprosthetic joint infection 45, and appears upregulated in major depressive disorder and idiopathic pulmonary fibrosis 67. Probiotic-induced DEFA4 upregulation correlates with improved depression outcomes 8. These associations suggest DEFA4 participates in immune surveillance mechanisms relevant to diverse inflammatory, infectious, and neuropsychiatric conditions.