NOTCH4 is a transmembrane receptor that functions as a critical regulator of cell fate determination through ligand-induced signaling. Upon activation by Jagged1, Jagged2, or Delta1, NOTCH4 releases its intracellular domain (NICD4), which forms a transcriptional activator complex with RBPJ to regulate genes controlling differentiation, proliferation, and apoptosis 1. Mechanistically, NOTCH4 functions as a mechanosensitive receptor that responds to disturbed blood flow in endothelial cells, with JAG1-NOTCH4 signaling regulating endothelial cell heterogeneity 1. NOTCH4 also operates through multiple signaling axes: in regulatory T cells, it suppresses amphiregulin production via interleukin-18 signaling, promoting inflammation 2, and upregulates GDF15 through Wnt/Hippo pathway activation 3. Additionally, NICD4 transcriptionally activates HES1 expression 4. Clinically, elevated NOTCH4 expression correlates with disease severity across multiple conditions: COVID-19 mortality and lung inflammation 2, asthma severity 3, and pulmonary tuberculosis progression 5. In kidney disease, Sirt6-mediated inhibition of Notch4 protects podocytes from injury and proteinuria 6. Conversely, NOTCH4 mutations can sensitize lung adenocarcinoma cells to EGFR-TKI therapy 4. Genetic polymorphisms associate with schizophrenia susceptibility and Alzheimer's disease risk 7, 8, suggesting NOTCH4 involvement in neuropsychiatric pathogenesis.