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This review illustrates the multifaceted roles of EZH2 in non-cancerous diseases, including autoimmunity, fibrosis, metabolic, and neurological disorders. It highlights key pathological events mediated by EZH2, such as immune imbalance, ECM deposition, and neuroinflammation, and introduces the “CDE3” therapy model as a conceptual strategy to enhance the specificity, efficacy, and safety of EZH2-targeted interventions.

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Renjing Jin, Jianlin Zhang, Yuqing Wang, Ziyu Chen, Xuan He, Xintong Zhang, Zhen Tan, Celina G Kleer, Ye Li, Deli Wang, Lixiang Xue

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