Background <p>Vascular calcification is a major pathological process driving cardiovascular morbidity and mortality, yet effective therapies are lacking. This study aims to identify novel causal plasma proteins and therapeutic targets for vascular calcification through an integrative multi-omics approach and to further explore their functional roles and regulatory mechanisms in vascular calcification.</p> Methods <p>We performed a high-throughput Mendelian randomization (MR) analysis using protein quantitative trait loci from two large-scale proteomic studies (deCODE and UKB-PPP) as genetic instruments. Summary-level data for vascular calcification were obtained from genome-wide association studies. Candidate proteins underwent rigorous sensitivity analyses, colocalization, and external replication. Transcriptomic data were analyzed to assess expression changes in calcified vascular smooth muscle cells. Functional validation and mechanism exploration was conducted in high-phosphate-induced human aortic smooth muscle cells (HASMCs) and a 5/6 nephrectomy mouse model of vascular calcification using siRNA, overexpression plasmids, and the pharmacological inhibitor NCT-503.</p> Clinical trial number <p>Not applicable.</p>