In the present study, we showed for the first time that circN4bp1 was overexpressed not only in macrophages of animal models but also in the PBMCs and monocytes from sepsis-induced ARDS patients, and it promoted M1 macrophage activation but inhibited M2 macrophage polarization through the circN4bp1-miR-138-5p-EZH2 axis. Here, EZH2 is linked to acute respiratory distress syndrome.