ACY-1215 ameliorates experimental colitis by inhibiting dendritic cell maturation and Th1/Th17 responses

To evaluate the therapeutic potential of ACY-1215, a selective histone deacetylase 6 inhibitor, in inflammatory bowel disease and to provide mechanistic insights into its effects on dendritic cell-driven T-cell responses.

A dextran sulfate sodium-induced murine colitis model was used to assess the effects of ACY-1215 on disease severity, colon injury, epithelial barrier integrity, and tight junction protein expression. Bulk transcriptomic profiling of colonic tissues was performed to identify altered immune pathways. A public single-cell RNA-seq dataset, GSE134809, was reanalyzed to obtain cell-type-resolved evidence. Functional assays were conducted to examine the effects of ACY-1215 on dendritic cell maturation, migration, and dendritic cell-mediated Th1/Th17 polarization.

ACY-1215 markedly alleviated DSS-induced colitis, as shown by reduced body weight loss, ameliorated colon shortening, attenuated histopathological injury, and restoration of tight junction protein expression. Bulk transcriptomic analysis indicated suppression of antigen-presentation programs, including reduced MHC-II-related signatures, following ACY-1215 treatment. Single-cell RNA-seq analysis implicated increased dendritic cell-T cell communication together with elevated Th1/Th17 immune programs in inflamed intestine. Consistently, ACY-1215 inhibited dendritic cell maturation and migration and consequently attenuated Th1 and Th17 polarization.

These findings support selective HDAC6 inhibition as an immunoepigenetic strategy that restrains dendritic cell-driven T-cell responses and promotes mucosal homeostasis, highlighting ACY-1215 as a mechanism-based therapeutic candidate for inflammatory bowel disease.