Tier 3 — preclinical

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

Demin Cheng, Wenxia Bu, Fengxu Wang, Yueyuan Jin, Rongzhu Liu, Rui Zhao, Xuehai Wang, Mengna Jiang, Jinping Shen, Xinhang Cheng, Zuming Chen, Li Zhu, Jinlong Li, Zhenzhong Ge, Shichen Miao, Haotian Xu, Xiaoyu Zhou, Dongming Wang, Xinyuan Zhao
Advanced Science 2026 13(46):e75782

Bibliography

PubMed
PMID 42160006
DOI
10.1002/advs.75782
Funding
Supported by National Natural Science Foundation of China grants 82574142, 82173554 and 82504379 and multiple Chinese national, provincial and institutional research programs.

Study snapshot

DesignHuman/mouse single-cell transcriptomic analysis plus mechanistic macrophage and pulmonary-fibrosis experiments.
ModelHuman and mouse silicosis lung tissues, macrophages and silica-induced fibrosis models.
Sample
InterventionMechanistic perturbation of the SIRT6-ATF3-importin alpha pathway and itraconazole blockade of ATF3 nuclear import.
DurationModel-specific.
EndpointsATF3 deacetylation and nuclear import; Macrophage senescence; Mitochondrial dysfunction; SPP1-CD44 fibroblast activation; Pulmonary fibrosis

What the study showed, in plain terms

In silicosis, SIRT6-mediated deacetylation of ATF3 promoted ATF3 nuclear entry, macrophage senescence and downstream fibroblast activation. This is a clear example in which a SIRT6 catalytic action contributed to disease rather than protection.

Key findings

The study links SIRT6-dependent ATF3 deacetylation to mitochondrial dysfunction, macrophage senescence and silica-induced fibrosis; blocking ATF3-importin alpha binding reduced fibrosis.

What this study can and cannot tell us

This is a disease-specific silicosis mechanism and does not show that systemic SIRT6 activation causes lung fibrosis generally. It is important counter-evidence to universal anti-fibrotic or anti-inflammatory framing.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability