While EZH2 has been extensively studied in tumor biology, accumulating evidence reveals its central role in regulating immune balance, fibrosis progression, energy metabolism, and neuronal homeostasis. Through H3K27me3-mediated chromatin remodeling, EZH2 modulates T cell polarization, fibroblast activation, andβ-cell regeneration, positioning it as a promising target across a spectrum of non-oncological disorders. Preclinical studies have shown that EZH2 inhibitors such as Tazemetostat, GSK126, and 3-DZNep exert anti-inflammatory, anti-fibrotic, and neuroprotective effects. To address limitations in clinical translation, the authors introduce the “CDE3” framework—integrating combination therapy, delivery optimization, targeted degradation, enzyme inhibition refinement, and early intervention—to expand therapeutic potential while minimizing off-target risks.
Key points of the review include：
- Autoimmune modulation: EZH2 dysregulation promotes Th17/Tfh differentiation and suppresses Treg activity, fueling chronic inflammation and pathogenic autoantibody production. It also activates fibroblast-like synoviocytes and inflammatory cytokines in RA and SLE.
- Fibrosis regulation: In liver, kidney, lung, and heart fibrosis, EZH2 exacerbates ECM deposition by silencing anti-fibrotic genes, inducing epithelial–mesenchymal transition (EMT), and polarizing macrophages toward the M2 phenotype.
- Metabolic reprogramming: EZH2 controls white-to-brown fat conversion,β-cell regeneration, and insulin sensitivity. Its inhibition alleviates obesity-induced inflammation and diabetic complications.
- Neuroinflammation and neuroprotection: EZH2 contributes to neurodegenerative processes in Alzheimer’s, Parkinson’s, and depression by suppressing neuroprotective genes and enhancing inflammation.
- CDE3 therapeutic model: The authors propose a five-component model:
• Combination therapy with anti-inflammatory or anti-fibrotic drugs
• Delivery optimization using nanocarriers or antibody-drug conjugates
• EZH2 direct degradation via PROTACs
• Enzymatic inhibition for precise, sustained suppression
• Early-stage intervention before irreversible damage occurs
This comprehensive review highlights EZH2’s transition from a cancer target to a systemic disease modulator and offers a roadmap for next-generation epigenetic therapy in chronic disease. The review titled “EZH2 in Non-Cancerous Diseases: Expanding Horizons” was published in Protein & Cell (published on May 19, 2025).
DOI：
https://doi.org/10.1093/procel/pwaf032