The emerging paradigms of SETD family enzymes as epigenetic regulators of the immune response in inflammatory diseases.

Family members of the SET domain family (SETD) of histone lysine methyltransferases (HKMTs) act as principal epigenetic regulators, modulating chromatin structure, transcription pathways, and immune responses. SETDs catalyze lysine methylation on histone and non-histone substrates, as well as non-histone proteins (e.g., p53, NF-κB). These biochemical modifications support gene activity requisite for directing immune cells, modulating cytokine cascades, and inflammatory responses. For SETD family members, systemic dysregulation has become the principal mechanistic fulcrum within the orchestration of major autoimmune and inflammatory syndromes, comprising rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), psoriasis, atherosclerosis and type 2 diabetes, and, to a lesser extent, multiple sclerosis (MS) and inflammatory bowel disease (IBD). SETD1A and SETD1B catalyze H3K4 methylation and regulate the chromatin states governing the proliferation of T-lymphocytes. SETD2 spatially regulates H3K36 trimethylation with the augmentation of DNA regulatory steps and cytokine signaling. SETD6 and SETD7, and other components, enhance the NF-κB signaling involving innate immune response and regulation of chromatin structure. Experimentally validated mutations transform transcript re-equilibration and catalysis of benign enzymes. These alterations disturb immune consistency and endorse predetermined inflammatory responses, and weaken self-tolerance. In the post-genomic era, integrated therapeutic approaches are emerging from potent SETD modulators, small inhibitors, epigenetic scissors, and multi-omics techniques. Overall, this review demonstrates the emerging domain of immuno-epigenetics, SETD enzymes, and the strategic value they could serve as therapeutic targets and biomarkers.