SIRT6-Mediated Deacetylation of ATF3 Promotes Silica-Induced Lung Fibrosis by Enhancing its Nuclear Import via Binding to Importin α.

Silicosis is the most common occupational lung disease caused by respirable crystalline silica inhalation, with limited therapeutic options. Cellular senescence plays a critical role in the pathogenesis of lung diseases, while the role of senescent macrophages in silicosis remains unclear. Single-cell RNA sequencing (scRNA-seq) of healthy and silicosis human and mouse lung tissues revealed that activating transcription factor 3 (ATF3)-mediated macrophage senescence is closely linked to silicosis progression. Mechanistically, Sirtuin 6 (SIRT6)-mediated ATF3 deacetylation enhanced its nuclear transport and subsequently activated mitochondria-localized glutamic acid-rich protein (MGARP) transcription, thereby causing mitochondrial dysfunction and macrophage senescence. Senescent macrophages promoted fibroblast activation via the secreted phosphoprotein 1 (SPP1)-cluster of differentiation 44 (CD44) signaling pathway. Furthermore, the nuclear transport protein importin α and the molecular chaperone protein heat shock protein 70 (HSP70) competitively bound to ATF3, preventing its lysosomal degradation while promoting its nuclear import during macrophage senescence. Moreover, the small-molecule inhibitor Itraconazole, which targets the binding site of ATF3 and importin α, could reduce ATF3 nuclear entry, macrophage senescence, and pulmonary fibrosis (PF). Collectively, our study provided insights into the mechanism by which deacetylated ATF3 facilitates silicosis progression via increased nuclear transport and macrophage senescence, and indicated potential therapeutic targets for PF.