The role and potential therapeutic application of HDAC6 inhibitors in inflammation-related diseases: A medicinal chemistry perspective.

Histone deacetylase 6 (HDAC6), as the most structurally and functionally unique member of the HDAC family, mediates the deacetylation process of various histone or non-histone substrates. Broad biological functions promote HDAC6 to involve a variety of physiological processes, particularly plays an important role in the pathological process of inflammation. HDAC6 activates the NF-κB signaling pathway through deacetylation, upregulating the expression of inflammation-related genes (e.g. TNF, NLRP3 and IL1B). Additionally, HDAC6 also participates in NLRP3 inflammasome activation through its ZnF-UBP domain, thereby resulting in the release of various inflammatory cytokines. Notably, several conventional HDAC6 inhibitors have exhibited promising therapeutic effects in various inflammation-related disease models. These findings underscore the potential of HDAC6 as a therapeutic target, and some explorations of novel HDAC6 inhibitors for treating inflammation have been reported recently. Herein, we summarized the critical role of HDAC6 in inflammation, highlight recent advances of HDAC6 inhibitors in inflammation treatment and propose some insights about future development from the perspective of medicinal chemistry, aiming to provide some guidance for the application of HDAC6 inhibitors in inflammation-related diseases.