This preprint identifies two microRNAs—miR487a-3p and miR6855-3p—as key drivers of atherosclerosis through their effects on macrophage behavior. Both microRNAs were significantly elevated in coronary artery disease patients versus healthy controls, with plasma levels correlating with blood lipids and disease severity. The researchers demonstrated these microRNAs promote pro-inflammatory macrophage polarization and foam cell formation by targeting CPE and RRM2 proteins respectively. Each microRNA showed diagnostic accuracy of 0.83 AUC for detecting coronary disease. This finding advances our understanding of atherosclerosis beyond traditional cholesterol-focused models by revealing how specific microRNAs orchestrate the inflammatory cascade within arterial walls. The research suggests these microRNAs could serve dual roles as both diagnostic biomarkers and therapeutic targets for cardiovascular disease. However, this work remains a preprint awaiting peer review, and the findings require validation in larger patient cohorts before clinical application. The mechanistic insights are particularly valuable given that macrophage dysfunction is central to both atherosclerosis progression and plaque rupture—the immediate cause of most heart attacks. This represents confirmatory research that deepens our molecular understanding of cardiovascular disease pathogenesis.