HDAC6 is a major cytoplasmic deacetylase. XBP1s is a basic-region leucine zipper (bZIP) transcriptional factor. Despite their mutual involvement in the anti-oxidative process, there are no reports about their inter-protein interactions so far. Here we identified a direct link between HDAC6 inhibition and XBP1s transcription activity in anti-oxidative damage. We showed that the specific HDAC6 inhibitor Tubastatin A could up-regulate XBP1s transcriptional activity, thereby increasing anti-oxidative genes expression. Moreover, knock down of XBP1s could significantly abolish the cell growth protection afforded by Tubastatin A. We hypothesize that Tubastatin A acts to increase XBP1s protein levels that are dependent on its HDAC6 deacetylase inhibition via a mechanism involving acetylation-mediated proteasomal degradation, providing novel mechanistic insight into the anti-oxidative effects of HDAC6 inhibition. (C) 2014 Elsevier Inc. All rights reserved.