Knockdown of CDCP1 Inhibits ox-LDL-Induced Phenotypic Transition and Lipid Accumulation in Vascular Smooth Muscle Cells via Downregulating the ITGB4/PI3K/AKT Pathway

The transition of vascular smooth muscle cells (VSMCs) toward a macrophage-like phenotype is a key event driving atherosclerosis (AS) progression. CUB domain-containing protein 1 (CDCP1) is involved in cellular remodeling and signal transduction, associated with cardiovascular pathology, but its function in AS is still unclear. Here, we investigated whether CDCP1 regulates VSMC macrophage-like phenotypic transition and lipid accumulation during AS progression. Differential expression analysis of the human vascular transcriptomic datasets GSE43292 and GSE28829 identified CDCP1 as a commonly upregulated gene in atherosclerotic plaque tissues. Immunohistochemical staining further confirmed increased CDCP1 expression in aortic arch plaques from high-fat diet-fed ApoE⁻/⁻ mice. In primary mouse VSMCs, siRNA-mediated CDCP1 knockdown suppressed ox-LDL-induced macrophage-like phenotypic transition, as shown by Western blot and immunofluorescence analysis. Oil Red O staining, BODIPY 493/503 staining and DiI-ox-LDL uptake assays further showed that CDCP1 silencing reduced lipid accumulation, lipid droplet formation and ox-LDL uptake. RNA sequencing followed by KEGG enrichment analysis demonstrated that CDCP1 knockdown modulated the PI3K/AKT pathway, with ITGB4 identified as a markedly downregulated upstream molecule. Mechanistically, CDCP1 silencing decreased ITGB4 expression mainly by reducing ITGB4 mRNA stability, thereby inhibiting PI3K/AKT pathway activation and limiting VSMC macrophage-like transition and lipid accumulation. Collectively, CDCP1 emerges as a key mediator of VSMC pathological remodeling and lipid loading, highlighting its potential as a molecular target for AS intervention.