Background <p>Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by excessive macrophage infiltration and extracellular matrix deposition. The progress of IPF is promoted by M2 macrophages which produce pro-fibrotic factors and induce fibroblast differentiation. SESN3 was upregulated in lung tissues of IPF patients and mice with bleomycin-induced pulmonary fibrosis. However, the role of SESN3 in IPF and its related mechanisms remain largely unknown.</p> Methods <p>Here, we used IL-4/13 to induce macrophage M2 polarization in RAW264.7 cells and constructed a mouse model of pulmonary fibrosis by intratracheal injection of bleomycin. Adenoviruses targeting SESN3 were constructed to infect RAW264.7 cells and BLM-induced mice to assess the function of SESN3 in macrophage M2 polarization in the progress of IPF and mRNA-seq and Co-IP-MS analysis were performed to find the downstream factors.</p> Results <p>For in vitro experiments, SESN3 knockdown promoted the M2 polarization level, the release of pro-fibrosis factors and the activation of fibroblast, overexpression of SESN3 had an opposite trend. For in vivo experiments, the increased degree of pulmonary fibrosis in BLM mice was relieved after overexpression of SESN3. Meanwhile, overexpression of SESN3 repressed the increased macrophage M2 polarization level induced by BLM. Mechanically, FOSL2 was screened out through mRNA-seq and Co-IP-MS analysis due to its binding affinity with SESN3 and the observed downregulation of its downstream pro-fibrotic factor expression. The expression of FOSL2 in the nucleus was down-regulated after SESN3 overexpression. Under IL-4/13 treatment, the increased levels of macrophage M2 polarization and pro-fibrotic factors induced by SESN3 knockdown was recovered after knocking down FOSL2 in RAW264.7 cells.</p> Conclusion <p>In summary, our study suggested that SESN3 regulated the IPF process through inhibiting macrophage M2 polarization by targeting the activity of FOSL2.</p>