CARD14 is a caspase recruitment domain protein that functions as a scaffold to regulate skin barrier homeostasis through dual signaling mechanisms. CARD14 signals via NF-κB to enhance the antimicrobial chemical barrier in keratinocytes 1, while also directly binding and regulating MYC to bolster the physical barrier function 1. Disease-associated CARD14 variants impair both pathways, compromising barrier integrity 1. In psoriasis pathogenesis, CARD14 dysfunction through dysregulation by UBA domain-containing proteins or indoleamine 2,3-dioxygenase 2 drives IL-17-dominant inflammation 2. CARD14 variants dysregulate the gut microbiota-immune axis, where indole-producing bacteria promote indoxyl sulfate biosynthesis, which signals through the aryl hydrocarbon receptor in skin Th17 cells to potentiate inflammation 3. CARD14 mutations are causally implicated in familial pityriasis rubra pilaris (Type V PRP) 45, with pathogenic variants also associated with atopic dermatitis and inflammatory linear verrucous epidermal nevus 6. In cancer, elevated CARD14 expression correlates with improved prognosis in sarcoma, lung, cervix, and head and neck cancers, and positively correlates with neutrophil infiltration 7. These findings establish CARD14 as a critical regulator of epithelial barrier function and immune homeostasis with implications across inflammatory and neoplastic diseases.