Abstract

Atherosclerosis is the leading cause of cardiovascular diseases worldwide. However, the molecular mechanisms underlying atherosclerosis remain incompletely understood. Here, we describe a previously unrecognized role of FES tyrosine kinase in macrophages and its therapeutic potential in atherosclerosis. First, we performed a proteome-wide Mendelian randomization analysis to investigate causal relationships between plasma proteins and atherosclerosis risk, utilizing GWAS data from FinnGen R10 and plasma protein data from the UK Biobank. Integrating Bayesian colocalization and single-cell expression profiling, we identified FES as a potential therapeutic target for atherosclerosis. We found that FES expression was significantly reduced in atherosclerotic plaques of ApoE −/− mice fed a high-fat diet. Notably, intravenous delivery of recombinant adeno-associated virus (rAAV)-mediated FES overexpression significantly reduced inflammatory responses and lipid deposition in atherosclerotic plaques. Computational predictions coupled with biochemical experiments revealed that FES-mediated atheroprotection is accomplished through upregulation of Arg1. Furthermore, we observed that FES increases Arg1 expression by activating the transcription factor PU.1 and promoting its nuclear translocation. In summary, our study is the first to identify a novel role and mechanism for FES in atherosclerosis and provides a promising therapeutic strategy for atherosclerosis.