Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a fatal and undertreated condition with severe inflammation, of which the molecular mechanisms remain largely unknown. Here we found a small molecule, 4-indole-2-arylaminopyrimidine (IAAP), suppressed the lipopolysaccharide (LPS)-induced inflammatory responses in airway epithelial cells, macrophages, and mouse lungs. Immunoprecipitation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified that IAAP interacted with cathepsin L (CTSL) and suppressed the lysosomal activity. Mechanistically, LPS triggered the maturations of CTSL and enhanced lysosomal activity, which resulted in the degradation of A20, a deubiquitylase critical for the IKK functions. IAAP suppression of CTSL eventually led to a significant accumulation of A20 and subsequently decreased K63-linked polyubiquitin chains (polyUb) of NEMO, thereby ameliorating the LPS-induced inflammation and ALI. This work reveals CTSL as a newfashioned regulator of the NF-?B signaling through interaction with A20 and suggests IAAP as a potential lead compound for developing novel drugs for ALI/ARDS.