JAG1 is a canonical Notch ligand that functions as a cell surface receptor that activates Notch signaling through proteolytic cleavage, enabling NOTCH intracellular domain translocation to the nucleus for target gene transcription 1. JAG1 plays critical roles in cell-fate determination across multiple organ systems, particularly in hematopoiesis, cardiovascular development, and bile duct formation 1. Mechanistically, JAG1-NOTCH interactions regulate endothelial cell heterogeneity and differentiation 2, hepatocyte maturation 3, and valve interstitial cell elastogenesis 4. Pathogenic JAG1 mutations cause Alagille syndrome, an autosomal dominant multisystem disorder primarily characterized by liver and cardiac/vascular disease 5. Most JAG1 variants result in loss-of-function, demonstrating that haploinsufficiency is disease-causing 1. JAG1 mutations also associate with tetralogy of Fallot and certain cancers 1. Additionally, JAG1-NOTCH4 mechanosensing in endothelial cells promotes atherosclerosis at sites of disturbed blood flow 2, while JAG1 expression in macrophages and endothelial cells contributes to early rheumatoid arthritis pathogenesis through TNF-dependent mechanisms 6. Currently, therapies for JAG1-associated diseases are supportive, with future potential for targeted Notch pathway augmentation 5. iPSC-derived organoid systems enable functional characterization of disease-causing JAG1 mutations 7.