NTN4 is a secreted guidance molecule involved in neural, vascular, and organ development. It promotes neurite elongation and axon guidance through its interactions with cell surface receptors, while also playing multifactorial roles in non-neuronal cells including endothelial and fibroblastic populations. Mechanistically, NTN4 activates the NF-κB signaling pathway to increase vascular endothelial cadherin expression and enhance endothelial barrier function 1. NTN4 has been implicated in multiple cancer types through distinct mechanisms. In breast cancer, eQTL colocalization analysis identified NTN4 as a candidate risk gene; risk-associated variants reduce NTN4 promoter activity, and NTN4 knockdown increases cell proliferation in vitro and tumor growth in vivo 2. Conversely, lower NTN4 expression in invasive breast carcinoma tissue correlates with poorer survival and reduced CD8+ T cell infiltration 3. In hepatocellular carcinoma, the miR-17-92 cluster, which targets NTN4, is upregulated and promotes tumor development 4. Recent evidence also suggests NTN4 contributes to osteoarthritis pathology in the infrapatellar fat pad and synovium by promoting pro-inflammatory cytokine production and potentially sensitizing sensory neurons 5, 6. A genetic signal near NTN4 has been associated with Tourette syndrome, an axon-guidance gene in the developing striatum 7. No targeted therapeutics specifically addressing NTN4 dysfunction are currently approved; future work may clarify whether modulating NTN4 expression or signaling could benefit cancer or inflammatory joint disease management.