KDM6B inhibition modulates monocyte activation and alleviates IMQ-induced psoriasis-like skin inflammation

Abstract Background Inflammatory monocytes are increasingly recognized as key amplifiers of psoriasis, yet the epigenetic drivers of their pathogenic signature remain unclear. The mechanisms linking epigenetic regulation to metabolic reprogramming in monocyte-driven inflammation in psoriasis are poorly defined. Methods We examined the expression and activity of the histone demethylase KDM6B in classical monocytes in the imiquimod (IMQ)-induced psoriasis model. Epigenetic changes were assessed by measuring H3K27me3 levels at inflammatory and metabolic gene promoters. Pharmacological inhibition of KDM6-family H3K27 demethylase activity after disease onset was performed using GSK-J4, a cell-permeable prodrug that is intracellularly converted to the active inhibitor GSK-J1. In parallel, inflammatory and metabolic transcriptional programs, bioenergetic profiles, immune cell recruitment to inflamed skin, and single-cell transcriptomic changes in myeloid populations were analyzed. Results KDM6B expression and KDM6A/B demethylase activity were increased in classical monocytes during IMQ-induced psoriasis-like inflammation. This was associated with reduced levels of the repressive histone mark H3K27me3, an epigenetic modification linked to chromatin compaction and transcriptional silencing, at the Il1b , Tnf, Pgam1 , Pgk1 , and Aldoa promoters, together with an enhanced inflammatory and glycolytic gene signature. GSK-J4 treatment after disease onset restored H3K27me3 at inflammatory and metabolic loci, suppressed Il1b and Tnf transcription, normalized bioenergetic profiles, and reduced monocyte and neutrophil recruitment to inflamed skin. Single-cell transcriptomic profiling further revealed that GSK-J4 treatment was associated with reduced cytokine-mediated signaling, glycolysis, and chemotaxis pathways in monocytes, while enriching antigen presentation modules, consistent with a shift toward a homeostatic, antigen-presenting surveillance program in myeloid cells and a regulatory T cell (Treg)-supportive milieu. Conclusions Collectively, our data identify KDM6B-associated epigenetic-metabolic remodeling as a component of inflammatory monocyte activation in IMQ-induced psoriasis-like inflammation. GSK-J4 treatment attenuated ongoing inflammation when initiated after disease onset. These findings support further investigation of KDM6-family demethylases as therapeutic targets in psoriasis-like inflammation.