Proteome, lysine acetylome and succinylome identify post-translational modification of STAT1 as a novel drug target in silicosis

Inhalation of crystalline silica dust induces incurable lung damage, silicosis and pulmonary fibrosis. However, the mechanisms of the lung injury remain poorly understood, with limited therapeutic options aside from lung transplantation. Post-translational modifications can regulate the function of proteins and play an important role in studying disease mechanisms. To investigate changes in post-translational modifications of proteins in silicosis, combined quantitative proteome, acetylome, and succinylome analyses were performed with lung tissues from silica-injured and healthy mice using liquid chromatography-mass spectrometry. Combined analysis was applied to the three omics datasets to construct a protein landscape. The acetylation and succinylation of the key transcription factor STAT1 were found to play important roles in the silica-induced pathophysiological changes. Modulating the acetylation level of STAT1 with geranylgeranylacetone (GGA) effectively inhibited the progression of silicosis. This report revealed a comprehensive landscape of post-translational modifications in silica-injured mouse, presented a novel therapeutic strategy targeting the post-translational level for silica-induced lung diseases.