Pulmonary fibrosis is a complex pathological process characterized by massive destruction of the structure of lung tissues and aggravated pulmonary function impairment. The underlying mechanisms of
pulmonary fibrosis are incompletely understood and therefore limited treatment options are available currently. Here, we report that
MLN4924, an NEDD8 activation enzyme (NAE) activity-inhibiting molecule, blocks the maintenance and progression of established
pulmonary fibrosis. We found that
MLN4924 acts against
bleomycin-induced
pulmonary fibrosis mainly at the early inflammatory stage. Pharmacologically targeting the neddylation of
Cullin-Ring
E3 ligase (CRL) by
MLN4924, significantly abrogated NF-κB responses, suppressed MAPK activity, and reduced secretion of TNF-α-elicited pro-inflammatory
cytokines and MCP1-induced
chemokines.
MLN4924 inhibited pro-inflammatory responses while maintaining or increasing the production of the anti-inflammatory mediators such as anti-inflammatory
interleukins (ILs) following
bleomycin administration, which is closely correlated to its blocking NF-κB-mediated signaling. Consistently, our studies identified
MLN4924 as a promising therapeutic drug for
pulmonary fibrosis and suggested a potential role of
MLN4924 that fine tunes the MAPK signaling pathway controlling the inflammatory reactions at the early stages of
pulmonary fibrosis. In addition, our findings may broaden the potential practical application of
MLN4924 as an effective therapeutic strategy against other
inflammation-associated diseases.