Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencaphalopathy (CADASIL) is a rare hereditary cerabrovascular disease caused by a NOTCH3 mutation.However,the underlying cellular and molecular mechanisms remain unidentified.Here,we generated non-integrative induced pluripotent stem calls (iPSCs) from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C＞T,p.R1076C).Vascular smooth muscle calls (VSMCs) differentiated from CADASIL-specific iPSCs showed gene expreasion changes associated with disease phenotypas,including activation of the NOTCH and NF-κB signaling pathway,cytoskeleton disorganization,and excessive call proliferation.In comparison,these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient’s iPSCs.Importantly,the abnormal upregulation of NF-κB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor,providing a potential therapautic strategy for CADASIL Overall,using this iPSCbased disease model,our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.