DEFA1B (defensin alpha 1B) is an antimicrobial peptide of the innate immune system with emerging roles in infectious and inflammatory diseases. As a defensin, DEFA1B functions as an antimicrobial molecule with direct antiviral activity; notably, it inhibits Zika virus replication primarily through extracellular mechanisms before viral cell entry 1. Beyond antiviral defense, DEFA1B modulates host cellular responses by interacting with origin recognition complex 1 (ORC1) to retard cell cycle progression 1, suggesting roles in controlling cellular proliferation during immune challenges. DEFA1B expression is significantly upregulated across multiple disease contexts. During active Behçet's disease with neurological involvement (neuro-Behçet's disease), DEFA1B and NLRP3 represent the most remarkably upregulated genes and serve as biomarkers for disease activity estimation 2. In thyroid orbitopathy, DEFA1B is overexpressed 3.05-4.14 fold in active disease, implicating it in innate immune-mediated orbital inflammation 3. Elevated DEFA1B predicts Crohn's disease development up to 16 years before diagnosis, ranking among the top nine predictive proteins in machine learning models (AUC 0.76-0.79) 4. Additionally, DEFA1B serves as a prognostic biomarker for sudden cardiac death and is identified as a hub gene in adult degenerative scoliosis 5, 6. These findings establish DEFA1B as a multifunctional innate immune mediator with significant biomarker potential for early disease detection and prognosis.