GPR15LG (G protein-coupled receptor 15 ligand), also known as C10orf99 or AP-57, is a multifunctional antimicrobial peptide with dual roles in innate immunity and inflammatory regulation. Primary Function: GPR15LG exhibits broad-spectrum antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus, Actinomyces), fungi (Aspergillus niger), mycoplasma, and lentivirus 1. It also functions as a chemokine-like ligand binding to GPR15 to mediate T cell migration to the large intestine 2. Mechanism: GPR15LG binds the orthosteric site of CXCR4, synergistically enhancing CXCL12-induced cell signaling and migration across immune and cancer cell types 3. In keratinocytes, it activates ERK1/2 and NF-κB pathways to promote proliferation and inflammatory cytokine expression (IL-1α, IL-1β, TNF-α) 45. Disease Relevance: GPR15LG is highly upregulated in psoriatic and atopic dermatitis lesions, where it reduces barrier-related genes and promotes keratinocyte proliferation 6. In inflammatory bowel disease, GPR15LG increases colitis susceptibility and colitis-associated colorectal cancer through both GPR15-dependent T cell migration and GPR15-independent epithelial barrier disruption 2. Clinical Significance: GPR15LG represents a potential therapeutic target for inflammatory skin diseases and IBD, with antimicrobial peptide formulations showing promise for wound healing applications 7.