ADGRL4 (adhesion G protein-coupled receptor L4), also known as ELTD1, is an endothelial orphan receptor functioning as a key regulator of angiogenesis 1. As an adhesion GPCR family member, ADGRL4 possesses a unique structure with a large extracellular domain and G protein-coupled receptor activity 1. In endothelial cells, ADGRL4 regulates physiological and tumor angiogenesis through non-canonical signaling mechanisms; while it couples weakly to heterotrimeric Gq protein, it does not activate canonical GPCR pathways 23. ADGRL4 overexpression promotes endothelial sprouting angiogenesis and regulates the tip-cell phenotype by modulating genes including JAG1, DLL4, and KIT, while affecting cellular metabolism through ACLY and SLC25A1 regulation 34. ADGRL4 is upregulated in the tumor microenvironment and implicated in multiple malignancies including glioblastoma, making it an attractive therapeutic target 2. Clinical relevance extends to sleep disorders, with ADGRL4 variants associated with chr1 determination 5, and breast cancer, where ADGRL4 expression correlates with HER2 status and disease stage, serving as a potential prognostic biomarker 6. Additionally, ADGRL4 is implicated in ALS/ALS-FTD pathology as a marker of vulnerable cortical neurons 7.