Background We recently reported the differential circRNAs expression patterns of the pulmonary macrophages in sepsis induced ARDS mice model by microarray analysis; However, their function and hidden molecular mechanism in regulation of macrophage activation and inflammation remains poorly understood. Methods In this study, serum were obtained from ARDS patients post sepsis and control subjects. Mice were subjected to Cecal ligation and puncture (CLP) surgery and intravenously injected with

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... ircN4bp1 plasmid transfected macrophages. Raw264.7 cells and MH-S cells were transfected with circN4bp1 overexpression or silence vectors and then polarized as M1 or M2 macrophages in vitro. Results We firstly examined the quantitative expression and localization of circN4bp1 in macrophages by Real-time PCR and fluorescence in situ hybridization (FISH), and found that circN4bp1 was overexpressed in PBMC and monocytes and its expression levels were correlated with a poor prognosis in ARDS patients induced by sepsis. In CLP-induced ARDS mice, we demonstrated that knockdown of circN4bp1 inhibited the lung injury and inflammatory cytokine release, and improved the long-time survival through blunting the M1 macrophage activation. Moreover, bioinformatics analysis predicated a circN4bp1/miR-138-5p ceRNA network, which was confirmed by Luciferase reporter assay and RNA binding protein immunoprecipitation (RIP). In vitro experiments, we indicated that circN4bp1 affected macrophage differentiation by binding to miR-138-5p, thus regulating the expression of EZH2. Lastly, we found that the m6A level of circN4bp1 was elevated in ARDS mice; inhibition of m6A methyltransferases METTL3 blocked this response in vitro. Conclusions These data suggest that circN4bp1 can function as a miR-138-5p sponge for the regulation of macrophage polarization and may serve as a potential target and/or prognostic marker for ARDS patients following sepsis.