EZH2 in non-cancerous diseases: expanding horizons

Abstract Enhancer of Zeste homolog 2 (EZH2), a histone methyltransferase within polycomb repressive complex 2 (PRC2), plays a crucial role in epigenetic regulation by silencing gene expression through trimethylation of histone 3 at lysine 27 (H3K27me3). Beyond its well-documented oncogenic functions, emerging research has revealed EZH2’s involvement in various non-cancerous pathologies. For instance, EZH2 is critical in regulating immune responses, particularly in modulating T cell differentiation and cytokine production, which affects inflammation and immune homeostasis. EZH2 also controls fibroblast activation and extracellular matrix (ECM) remodeling, influencing critical processes such as cell differentiation, tissue repair and energy homeostasis. Additionally, EZH2’s epigenetic regulation of neuroinflammatory processes is linked to neuronal health and survival. Recent advancements in EZH2 inhibitor therapies demonstrate promising potential for treating a range of non-cancerous conditions, with preclinical trials suggesting efficacy in mitigating disease progression. This review highlights the expanding functional scope of EZH2, emphasizing its epigenetic mechanisms and the therapeutic opportunities for targeting EZH2 in non-cancerous diseases.