<p>To explore the function and potential mechanism of laccase domain-containing 1 (LACC1) on atherosclerosis (AS). ApoE^−/− mice feed with high-fat diet (HFD) were injected with adenovirus shLACC1 (Ad-shLACC1) or Ad-shNC via tail vein. LACC1 was highly expressed in macrophages of atherosclerotic plaque in ApoE^−/− mice and ox-LDL-treated Raw264.7 macrophages. LACC1 silencing enhanced AS development and facilitated inflammation in mice. Then, we found that LACC1 silencing facilitated inflammation but repressed polyamine immunometabolism in ox-LDL-treated Raw264.7 macrophages. Through rescue experiments using ornithine or ODC1 inhibitor (DFMO), we further confirmed that LACC1 promoted polyamine immunometabolism to inhibit inflammation in ox-LDL-treated Raw264.7 macrophages. In addition, the observed LACC1 function was dependent on NOS2. In conclusion, we proved that the downregulation of LACC1 promoted AS progression via inhibiting polyamine immunometabolism in inflammatory macrophages, suggesting LACC1 may be a potential therapeutic target for AS.</p> Graphical Abstract <p></p>