<p>Atherosclerosis remains a leading cause of cardiovascular disease and mortality worldwide, despite advancements in statin therapies. Here, we aimed to identify potential anti-atherosclerosis drugs by an integrated approach combining network medicine-based prediction with empirical validation. Among the top drugs predicted by the preferred algorithm, mesalazine─a drug traditionally used to treat inflammatory bowel disease, was selected for in vivo validation in ApoE^−/− mouse model of atherosclerosis. After an 8-week treatment period, mesalazine significantly inhibited atherosclerosis progression by reducing total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels, while increasing high-density lipoprotein cholesterol (HDL-C) levels. Additionally, it decreased the plaque area and hepatic steatosis. Gene expression analysis via RT-qPCR revealed that mesalazine downregulated key genes associated with atherosclerosis. These findings highlight the potential of mesalazine as a repurposed anti-atherosclerosis drug and offer novel insights into drug screening for atherosclerosis treatment.</p> Graphical Abstract <p></p>