ArticleClinical epigenetics2026
Histone H3K27 demethylation drives Crohn's disease inflammation: GSK-J4 as a potential epigenetic therapy.
Article in Clinical epigenetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundCrohn's disease (CD) is characterised by recurrent gastrointestinal inflammation. Epigenetic modifications, particularly the methylation of histone H3 at lysine 27 trimethylation (H3K27me3), are crucial in regulating gene expression and macrophage activity. Dysregulation of these modifications may contribute to CD pathogenesis.
objectiveTo investigate the role of H3K27me3 in CD, assess the involvement of the WNK1-TAK1 signalling pathway, and evaluate the therapeutic potential of GSK-J4, a selective histone demethylase inhibitor.
methodsPeripheral blood and intestinal tissue were collected from CD patients (n = 19) undergoing surgical resection and from age-matched healthy controls (HC, n = 17). Monocytes were isolated and differentiated into macrophages. Expression of H3K27me3, demethylases KDM6A and KDM6B, and components of the WNK1-TAK1 pathway were assessed by Immunofluorescence, Western blotting, and qRT-PCR. GSK-J4 was used to assess its effect on these markers and cytokine secretion.
resultsInflamed CD tissue and derived macrophages showed increased KDM6A/B expression and reduced H3K27me3 compared with unaffected tissue and HC-derived macrophages. GSK-J4 treatment reversed this epigenetic profile and significantly reduced secretion of inflammatory cytokines IL-6, IL-10, and TNF-α. Activation of the WNK1-TAK1 axis was identified as a key mediator of lipopolysaccharide-induced cytokine release and was modulated by GSK-J4.
conclusionThis study identifies KDM6A/B-driven epigenetic dysregulation as a novel pathogenetic mechanism in CD. GSK-J4 effectively restores H3K27me3 levels and reduces inflammation, supporting histone demethylase inhibition as a promising and mechanistically novel therapeutic approach warranting further translational investigation.
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