IL17C is a cytokine that functions as a key mediator of innate epithelial immunity, particularly against intestinal bacterial pathogens through autocrine signaling. It stimulates production of antibacterial peptides and pro-inflammatory molecules via NF-κB and MAPK pathways, acting synergistically with IL22, TNF, and IL1B to induce antimicrobial responses including S100A8, S100A9, REG3A, REG3G, and DEFB2 1. IL17C plays a complex dual role: it maintains epithelial homeostasis during inflammatory challenge but can also promote pathogenic inflammation, and enhanced IL17C/IL17RE signaling is associated with increased autoimmune disease susceptibility. In inflammatory bowel disease, DUOX2 loss-of-function variants associate with elevated plasma IL-17C levels and intestinal dysbiosis with pathogenic Proteobacteria, representing a preclinical hallmark of disturbed microbiota-immune homeostasis 2. IL17C is elevated in inflammatory skin diseases including hidradenitis suppurativa, where dermal tunnel keratinocytes express IL17C in a pattern distinct from epidermis 3. Elevated IL-17C has been detected in atopic dermatitis lesions and is reduced following dupilumab therapy 4. Recent evidence suggests IL-17C also participates in gut-brain axis dysregulation, with elevated intestinal IL-17C linked to nanoplastic-induced neurotoxicity that is reversible with anti-IL-17C antibodies 5. Therapeutically, IL-17 pathway inhibitors including secukinumab, ixekizumab, brodalumab, and bimekizumab target IL-17 family members and have been approved for psoriasis, hidradenitis suppurativa, and spondyloarthropathies 6.