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Multi-walled carbon nanotubes (MWCNTs) have been developed with numerous beneficial applications. However, rodent models demonstrate that exposure to MWCNTs via respiratory pathways results in pulmonary fibrosis. Therefore, they could elicit a potential risk of pulmonary fibrosis in humans due to occupational or consumer exposure. Sirtuin 6 (SIRT6), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, has been proved to prevent fibrosis in the liver, renal and myocardial tissues. In this present study, we aimed to explore the role of SIRT6 in MWCNTs-induced epithelial-mesenchymal transition (EMT), one of the major contributor of lung fibrogenesis in human bronchial epithelial BEAS-2B cells. We found that the protein level of SIRT6 was elevated after exposure to MWCNTs in BEAS-2B cells. Overexpression of SIRT6 significantly inhibited MWCNTs-induced EMT and EMT-like cell behaviors in BEAS-2B cells. Moreover, wild-type SIRT6 was found to decrease MWCNTs-induced phosphorylation of Smad2, but not mutant SIRT6 (H133Y) without histone deacetylase activity. In conclusion, our study demonstrated that SIRT6 inhibited MWCNTs-induced EMT in BEAS-2B cells through TGF-β1/Smad2 signaling pathway, which depended on its deacetylase activity, and provided evidences that targeting SIRT6 could be a potential novel therapeutic strategy for MWCNTs-induced pulmonary fibrosis. • Sirtuin 6 (SIRT6) was elevated after exposure to MWCNTs in BEAS-2B cells. • SIRT6 overexpression inhibited MWCNTs-induced epithelial-mesenchymal transition (EMT). • SIRT6 inhibited EMT via TGF-β1/Smad2 pathway, depending on its deacetylase activity. • SIRT6 is a promising target to protect against MWCNTs-induced pulmonary fibrosis. [ABSTRACT FROM AUTHOR]