Importantly, endothelium-specific supplementation with Aff3ir-ORF2 effectively attenuated endothelial activation and reduced the atherosclerotic plaque area in Apoe-/- mice, suggesting that targeting endothelial Irf5 activation with Aff3ir-ORF2 holds promise for the treatment of atherosclerosis. Here, IRF5 is linked to atherosclerosis.