Human β-defensin-3 as a transcriptional convergence point linking innate immunity, endocrine signals, and tissue repair.

Human β-defensin 3 (hBD-3) is a multifunctional host defense peptide with exceptional antimicrobial, immunomodulatory, and tissue-repair properties. Beyond its potent activity against gram-positive and gram-negative bacteria, fungi, and selected viruses, hBD-3 plays a central role in epithelial barrier integrity, chemotactic signaling, and wound healing. Its expression is tightly regulated by an intricate network of pattern-recognition receptors, inflammatory cytokines, growth factors, vitamins, and endocrine mediators. Emerging evidence indicates that hBD-3 functions as a transcriptional convergence point, integrating signals from NF-κB, AP-1, STATs, and nuclear receptors to coordinate antimicrobial and immune responses. Notably, glucocorticoids selectively modulate hBD-3 in ways that differ from other defensins, suggesting unique regulatory mechanisms within immune-endocrine environments. hBD-3 also contributes to angiogenesis, fibroblast activation, and keratinocyte migration, supporting its role in tissue repair and chronic wound management, including in diabetic microenvironments. Recent promoter analyses further reveal potential non-classical regulatory elements that expand current understanding of hBD-3 transcriptional control. Despite these advances, therapeutic manipulation of hBD-3 remains controversial due to its context dependent immunologic effects, potential oncogenic implications, and delivery challenges. This review synthesizes current knowledge on hBD-3 biology, regulation, and function, and discusses the opportunities and limitations for its therapeutic application in infectious and inflammatory diseases.