UNC5CL (unc-5 family C-terminal like) is a death domain-containing protein that functions as a MyD88-independent activator of pro-inflammatory signaling pathways. The protein activates NF-κB and c-Jun N-terminal kinase pathways through IRAK1, IRAK4, and TNF receptor-associated factor 6, but notably operates independently of MyD88 1. UNC5CL undergoes constitutive autoproteolytic processing and is specifically anchored to the apical surface of mucosal epithelial cells, where it induces expression of pro-inflammatory chemokines including IL-8, CXCL1, and CCL20 1. The protein's prominent expression in mucosal tissues suggests involvement in epithelial inflammation and immunity, making it a candidate gene for mucosal diseases such as inflammatory bowel disease 1. Recent studies have identified UNC5CL as a mediator of inflammation in diabetic kidney disease, where it promotes inflammatory responses through interaction with aldehyde dehydrogenase-1 L1 2. Additionally, UNC5CL has emerged as a potential Alzheimer's disease risk gene, with genetic variants associated with cognitive resilience and neurodegeneration 34. The protein has also been implicated in irritable bowel syndrome pathogenesis through network analysis studies 5.