Identification of PSMA4 as a Therapeutic Target for Atherosclerosis: A Comprehensive Multiomics Mendelian Randomization Analysis

Purpose Atherosclerosis (AS) is a leading cause of cardiovascular disease, and current treatments often fail to induce plaque regression. This study aims to identify novel, genetically supported therapeutic targets for AS to enable more effective drug development. Methods We employed an integrative multiomics framework, primarily using summary‐data‐based Mendelian randomization (SMR) to assess causal relationships between druggable genes and AS. We combined GWAS data for AS with blood cis‐expression quantitative trait loci (cis‐eQTL) data from three independent cohorts. Promising candidates were rigorously validated using external AS datasets, cross‐tissue cis‐eQTLs, two‐sample MR, colocalization, and linkage disequilibrium score regression (LDSC). Further multiomics validation incorporated cis‐methylation QTL (cis‐mQTL) and cis‐splicing QTL (cis‐sQTL) data. We evaluated target safety via phenome‐wide association study (PheWAS) and characterized cellular expression in atherosclerotic plaques using single‐cell RNA sequencing (scRNA‐seq). Finally, we predicted candidate therapeutics using the DGIdb database. Results SMR screening nominated PSMA4 as a top candidate, a finding consistently replicated across external cohorts and tissues. Two‐sample MR confirmed a causal effect of PSMA4 on AS risk, which was supported by strong colocalization evidence (PP.H4 = 0.941). Multiomics analyses revealed that a specific methylation site and a splicing site of PSMA4 influence AS risk by regulating its expression. LDSC indicated a significant shared genetic basis. PheWAS suggested a favorable safety profile, and scRNA‐seq pinpointed high PSMA4 expression in plaque immune cells like macrophages and dendritic cells. Drug prediction identified several proteasome inhibitors, including carfilzomib and bortezomib, as potential therapeutics. Conclusion This study establishes PSMA4 as a promising therapeutic target for AS, with robust genetic causality and a potential path for drug repurposing.