Abstract Body: The integrated regulation of microRNAs (miRNAs) on macrophage plasticity plays a key role in atherosclerosis (AS). We tested the hypothesis that miR487a-3p and miR6855-3p accelerate AS by promoting inflammation and lipid disorders in macrophages. The miRNAs with significant differences (miRNA-seq) in peripheral monocytes between coronary artery diseases (CAD) patients and controls (Ctrls) were validated by qPCR, verifying the increases of miR487a-3p and miR6855-3p in CAD group (VS. Ctrl). And they could be induced by oxidized low-density lipoprotein (ox-LDL) in human monocyte-derived and THP1-derived macrophages (TDMs) through the transcription factors, KLF5 (miR487a-3p) and IRF1 (miR6855-3p), along with the secretion in the supernatant. Accordingly, CAD patients (VS. Ctrls) exhibited remarkably increase of plasma miR487a-3p and 6855-3p that positively correlated to blood lipid levels and Gensini score (severity and prognosis of CAD). And the area under the receiver operating characteristic curve (»0.83 for each) evidenced the diagnostic accuracy. The expanded macrophages (miR487a-3p⁺ or miR6855-3⁺) and the elevated miRNA expressions in coronary arteries were positively associated with lesion area in CAD patients. Transcriptomic analyses and cell functional assay revealed that miR487a-3p or miR6855-3p promoted macrophage pro-inflammatory response and lipid metabolic dysregulation in TDMs. Conversely, inhibition of their expressions alleviated ox-LDL-induced macrophage inflammation and lipid retention. The intersection of mRNA-seq data with monocytes and TDMs and luciferase report assay identified Carboxypeptidase E (Cpe) and ribonucleotide reductase M2 subunit (Rrm2) as their targets. Overexpression CPE or RRM2 partially reversed the detrimental effects on TDMs induced by miR487a-3p and miR6855-3p respectively. However, monocyte/macrophage specific CPE or RRM2 depletion aggravated AS in PCSK9 overexpression mice on high fat diet. We conclude miR487a-3p and miR6855-3p fulfil the criteria of promising biomarkers for CAD diagnosis and prognosis, while they mechanistically intensify inflammation and disrupt lipid metabolism in macrophages, suggesting both of them as potential targets for CAD treatment.