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Cellular senescence plays a critical role in the pathogenesis of lung diseases, while the role of senescent macrophages in silicosis remains unclear. Single\u2010cell RNA sequencing (scRNA\u2010seq) of healthy and silicosis human and mouse lung tissues revealed that activating transcription factor 3 (ATF3)\u2010mediated macrophage senescence is closely linked to silicosis progression. Mechanistically, Sirtuin 6 (SIRT6)\u2010mediated ATF3 deacetylation enhanced its nuclear transport and subsequently activated mitochondria\u2010localized glutamic acid\u2010rich protein (MGARP) transcription, thereby causing mitochondrial dysfunction and macrophage senescence. Senescent macrophages promoted fibroblast activation via the secreted phosphoprotein 1 (SPP1)\u2010cluster of differentiation 44 (CD44) signaling pathway. Furthermore, the nuclear transport protein importin \u03b1 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\u2010molecule inhibitor Itraconazole, which targets the binding site of ATF3 and importin \u03b1, 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.<\/jats:p>","DOI":"10.1002\/advs.75782","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:53:08Z","timestamp":1779288788000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SIRT6\u2010Mediated Deacetylation of ATF3 Promotes Silica\u2010Induced Lung Fibrosis by Enhancing its Nuclear Import via Binding to Importin \u03b1"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9159-5340","authenticated-orcid":false,"given":"Demin","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine Affiliated Hospital of Nantong University School of Public Health Nantong 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