Novel Histone Deacetylase 6 Inhibitor Confers Anti-inflammatory Effects and Enhances Gut Barrier Function

Gut Liver. 2023 Sep 15;17(5):766-776. doi: 10.5009/gnl220159. Epub 2022 Sep 27.


Background/aims: The purpose of the current study was to examine the anti-inflammatory effects of CKD-506, a novel histone deacetylase 6 inhibitor, on human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells and to explore the relationship between CKD-506 and gut epithelial barrier function.

Methods: Lipopolysaccharide-stimulated human PBMCs from inflammatory bowel disease (IBD) patients were treated with CKD-506, and tumor necrosis factor (TNF)-α expression was measured using an enzyme-linked immunosorbent assay. The proliferation of CD4+ T cells from IBD patients was evaluated using flow cytometric analysis. The effects of CKD-506 on gut barrier function in a cell line and colon organoids, based on examinations of mRNA production, goblet cell differentiation, and E-cadherin recovery, were investigated using quantitative reverse transcription polymerase chain reaction, immunofluorescence, and a fluorescein isothiocyanate-dextran permeability assay.

Results: Secretion of TNF-α, a pivotal pro-inflammatory mediator in IBD, by lipopolysaccharide-triggered PBMCs was markedly decreased by CKD-506 treatment in a dose-dependent manner and to a greater extent than by tofacitinib or tubastatin A treatment. E-cadherin mRNA expression and goblet cell differentiation increased significantly and dose-dependently in HT-29 cells in response to CKD-506, and inhibition of E-cadherin loss after TNF-α stimulation was significantly reduced both in HT-29 cells and gut organoids. Caco-2 cells treated with CKD-506 showed a significant reduction in barrier permeability in a dose-dependent manner.

Conclusions: The present study demonstrated that CKD-506 has anti-inflammatory effects on PBMCs and CD4 T cells and improves gut barrier function, suggesting its potential as a small-molecule therapeutic option for IBD.

Keywords: Barrier function; HDAC6 inhibitor; Inflammatory bowel diseases; T-cell.

MeSH terms

  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Caco-2 Cells
  • Cadherins / metabolism
  • Cadherins / pharmacology
  • Cadherins / therapeutic use
  • Histone Deacetylase 6 / metabolism
  • Histone Deacetylase 6 / pharmacology
  • Histone Deacetylase 6 / therapeutic use
  • Humans
  • Inflammatory Bowel Diseases* / drug therapy
  • Inflammatory Bowel Diseases* / pathology
  • Intestinal Mucosa / pathology
  • Leukocytes, Mononuclear / metabolism
  • Lipopolysaccharides / metabolism
  • Lipopolysaccharides / pharmacology
  • Lipopolysaccharides / therapeutic use
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha*


  • Tumor Necrosis Factor-alpha
  • Histone Deacetylase 6
  • CKD-506
  • Lipopolysaccharides
  • Cadherins
  • RNA, Messenger
  • Anti-Inflammatory Agents