Abstract
Biofilm-associated infections remain among the most persistent global health challenges because of their inherent resistance to antibiotics and ability to evade host immune responses. Antimicrobial peptides (AMPs), especially those induced by vitamin D, have emerged as promising innate immune effectors with significant anti-biofilm activity. Vitamin D regulates the expression of key AMPs, including cathelicidin (LL-37) and human β-defensins, through vitamin D receptor-mediated transcriptional activation, thereby strengthening epithelial and immune defenses against microbial biofilms. This review synthesizes current understanding of the vitamin D signaling pathway, vitamin D-responsive AMPs, and their mechanisms of action against biofilms produced by clinically significant pathogens. Evidence from in vitro, in vivo and clinical studies is critically assessed, and emerging therapeutic approaches, such as vitamin D supplementation, topical applications, AMP analogs, and synergistic antimicrobial combinations are examined. Despite notable progress, challenges remain regarding AMP stability, delivery, and safety. The review concludes by outlining future directions, including engineered vitamin D analogs, nanotechnology-based delivery systems, and AMP-centered precision therapies as next-generation strategies to combat biofilm-associated infections.