The diphenylpyrimidine derivative as a novel HDAC6 inhibitor alleviates atopic dermatitis through anti-inflammatory effects facilitated via TLR4/MAPK, STAT3 and NF-κB pathways.

Atopic dermatitis (AD) is a systemic immune disease that primarily affects infants and children, characterized by recurring severe pruritus and chronic eczema. Studies have demonstrated that histone deacetylase 6 inhibitors (HDAC6is) can exhibit anti-inflammatory activities by regulating the acetylation level of target proteins. Building on these findings, our research focused on a synthetic diphenylpyrimidine derivative, specifically 15b, which we identified as a potent HDAC6i and an effective anti-inflammatory agent. This designation was determined by its safety profile, HDAC6 inhibitory activity, selectivity, and its anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. In 2,4-dinitrochlorobenzene (DNCB)-induced AD mice, daily intraperitoneal injections of 15b significantly alleviated symptoms such as skin edema, dryness, crusting, and peeling, and reduced the frequency of scratching. Moreover, 15b mitigated ear swelling, addressed the increase in epidermal thickness, and reduced mast cell infiltration. Further mechanistic studies revealed that 15b selectively inhibited HDAC6, enhanced the acetylation of α-tubulin and heat shock protein 90 (HSP90) in RAW264.7 cells and BALB/c mice back skin tissue, and attenuated the activation of TLR4/MAPK, STAT3, NF-κB pathways. Consequently, both inflammatory cytokines (IL-4 and IFN-γ) and proteins (iNOS and COX-2) were dose-dependently decreased. These findings suggest that the HDAC6 inhibitor 15b can serve as a potential anti-inflammatory agent for the treatment of AD.