The inflammatory response is tightly regulated, but its regulatory principles are still incompletely understood. Cyclophilin A (CypA) has long been considered as a pro-inflammatory factor. Here, we discover how CypA precisely regulates interleukin-1b (IL-1b)-mediated inflammatory responses. In lipopolysaccharide-treated mice, CypA deficiency initially inhibits and then promotes lung inflammation, which is closely related to IL-1b production. Mechanistically, CypA not only facilitates pro-IL-1b processing by increasing Smurf1-mediated K63-linked ubiquitination in an ATP-dependent manner but also accelerates pro-IL-1b degradation, depending on Smurf1-mediated K48-linked ubiquitination. Moreover, in IL-1b-treated mice, CypA exacerbates lung injury by enhancing cytokine production. It also upregulates the ILK/AKT pathway by inhibiting Cyld-mediated K63-linked ILK deubiquitination, which promotes the epithelial-mesenchymal transition (EMT) to facilitate lung repair. Collectively, CypA promotes inflammation activation by increasing IL-1b production and then promotes inflammation resolution by enhancing redundant pro-IL-1b degradation and IL-1b-induced EMT, indicating the compleix and delicate regulation of inflammatory response.