NOTCH3 is a transmembrane receptor that functions as a critical regulator of cell-fate determination through ligand-dependent signaling. Upon activation by membrane-bound ligands including Jagged1, Jagged2, and Delta1, NOTCH3 releases its intracellular domain (NOTCH3-ICD), which translocates to the nucleus and forms a transcriptional complex with RBPJ and MAML1 co-activators to regulate target gene expression 12. This canonical pathway controls diverse cellular processes including proliferation, differentiation, and apoptosis across multiple tissues. Clinically, NOTCH3 mutations cause CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), the most common hereditary cerebral small-vessel disease 3. NOTCH3 mutations, particularly those altering cysteine residue content in the extracellular domain, trigger structural abnormalities in vascular smooth muscle cells, leading to arterial degeneration and cerebrovascular failure 4. CADASIL typically presents in middle age with recurrent subcortical ischemic strokes, cognitive decline progressing to vascular dementia, and migraine with aura 5. Beyond cerebrovascular disease, NOTCH3 signaling controls placental trophoblast progenitor expansion and self-renewal 2, and elevated NOTCH3 expression correlates with poor prognosis in bladder and breast cancers, promoting malignant progression through downstream pathways including SPP1-PI3K/AKT signaling 67. NOTCH3 also regulates vascular smooth muscle cell proliferation in pulmonary arterial hypertension 8.