NOTCH2 is a transmembrane receptor that regulates cell fate determination through ligand-induced signaling. Upon activation by membrane-bound ligands JAG1, JAG2, or DLL1, NOTCH2 releases its intracellular domain (NICD), which forms a transcriptional complex with RBPJ to activate enhancer of split genes 12. The receptor controls differentiation, proliferation, and apoptosis programs and is critical for bone remodeling through enhanced osteoclast differentiation via NFATc1 3. NOTCH2 mutations cause Alagille syndrome, an autosomal dominant multisystem disorder characterized by dysfunctional Notch signaling; NOTCH2 variants account for a subset of cases, with missense mutations predominating 45. In immune development, NOTCH2 is essential for splenic marginal zone B cell development, dendritic cell differentiation, and helper T cell divergence 6. Human-specific NOTCH2NL paralogs expand cortical neurogenesis by promoting radial glia progenitor maintenance through enhanced Notch pathway activation, potentially contributing to human brain evolution 78. Clinically, NOTCH2 dysregulation drives cancer progression: elevated NOTCH2 translation promotes breast cancer metastasis via the YTHDF3 axis 9, while the DLL4-NOTCH2 pathway mediates anti-PD-1 resistance in bladder cancer 10. Loss-of-function NOTCH2 mutations promote ovarian cancer cell proliferation and invasion through reduced apoptosis and increased NF-κB signaling 11.