The glycyl-l-histidyl-l-lysine-Cu2+ tripeptide complex attenuates lung inflammation and fibrosis in silicosis via targeting peroxiredoxin 6

Silicosis is the most common type of pneumoconiosis, with a high incidence in workers chronically exposed to crystalline silica (CS). There is no specific drug to cure it. GHK, a tripeptide naturally occurring in human blood and urine, has been shown to have antioxidant effects. The aim of this study was to investigate the therapeutic effect of GHK-Cu on silicosis and its potential molecular mechanism. An experimental silicosis mouse model was established to observe the effects of GHK-Cu on lung inflammation and fibrosis. In addition, the effects of GHK-Cu on alveolar macrophages (AM) were examined in the raw264.7 cell line. Its molecular target, peroxiredoxin 6 (PRDX6), has been identified by chemical biology, and GHK-Cu can bind to PRDX6 and thus attenuate the reduction of lung inflammation and fibrosis in silicosis mice without significant systemic toxicity. These effects were partly related to the inhibition of CS-induced oxidative stress in AM by GHK-Cu. Thus, our results suggest that GHK-Cu acts as a potential drug by attenuating alveolar macrophage oxidative stress. This in turn attenuates the progression of pulmonary inflammation and fibrosis, which provides a therapeutic avenue for the prevention and treatment of silicosis.