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HDAC6 is a member of the class II histone deacetylase. HDAC6 inhibition possesses anti-inflammatory effects. However, the effects of HDAC6 inhibition in acute lung inflammation have not been studied. Here, we investigated the effects of a highly selective and potent HDAC6 inhibitor CAY10603 in LPS-induced acute inflammatory lung injury. We also conducted a series of experiments including immunoblotting, ELISA, and histological assays to explore the inflammatory signaling pathways modulated by the selective HDAC6 inhibition. We observed that HDAC6 activity was increased in the lung tissues after LPS challenge, which was associated with a decreased level of α-tubulin acetylation in the lung tissues. HDAC6 inhibition by CAY10603 prevented LPS-induced α-tubulin deacetylation in the lung tissues. HDAC6 inhibition also exhibited protective effects against LPS-induced acute lung inflammation, which was demonstrated by the reduced production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and decreased leukocyte infiltration. Furthermore, HDAC6 inhibition blocked the decrease of E-cadherin level and inhibited the increase of MMP9 expression in the lung tissues, which could prevent the destruction of the lung architecture in LPS-induced inflammatory injury. Given the important roles of NFκB and inflammasome activation in inflammatory responses, we investigated their regulation by HDAC6 inhibition in LPS-induced lung injury. Our results showed that HDAC6 inhibition blocked the activation of NFκB by inhibiting IκB phosphorylation in LPS-induced acute lung injury, and LPS-induced-inflammasome activity was reduced by HDAC6 inhibition as demonstrated by the decreased IL-1β and caspase-1 cleavage and activation. Collectively, our data suggest that selective HDAC6 inhibition suppresses inflammatory signaling pathways and alleviates LPS-induced acute lung inflammation.Increased HDAC6 activity is associated with lung α-tubulin deacetylation.HDAC6 inhibition prevents α-tubulin deacetylation in LPS-induced lung injury.HDAC6 inhibition protects against LPS-induced acute lung inflammation.HDAC6 inhibition blocks IκB phosphorylation.LPS-induced lung caspase-1 activation is reduced by HDAC6 inhibition.