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

Here, we demonstrate that the histone demethylase KDM6B is markedly upregulated and catalytically active in classical monocytes during the imiquimod (IMQ)-induced psoriasis model. This is 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.

Pharmacological blockade of KDM6B after disease onset using GSK-J4, a cell-permeable prodrug that is intracellularly converted to the active KDM6B inhibitor GSK-J1, restores H3K27me3 at inflammatory and metabolic loci, suppresses Il1b/Tnf transcription, normalizes bioenergetic profiles, and reduces monocyte and neutrophil recruitment to the inflamed skin. Single-cell transcriptomic profiling further reveals that KDM6B inhibition represses cytokine-mediated signaling, glycolysis, and chemotaxis pathways in monocytes, yet enriches antigen presentation modules, consistent with a shift toward a homeostatic, antigen-presenting surveillance program in myeloid cells and a Treg-supportive milieu.