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.

Renal fibrosis is a common mechanism leading to kidney failure in chronic kidney diseases (CKDs), including obstructive nephropathy (ON). Dysregulated inflammation is central to the development of renal fibrosis, but how local immune cells within the tissue microenvironment integrate and coordinate to drive this condition remains largely unknown. Herein, we documented that neutrophils were abundantly recruited and expelled neutrophil extracellular traps (NETs) in human and mouse fibrotic kidneys. Importantly, circulating levels of NETs components displayed a significant correlation with worsened kidney function in ON patients. In the unilateral ureteral obstruction (UUO) mouse model, blocking NETs by protein-arginine deiminase type 4 (PAD4) deletion or DNase treatment significantly impaired NETs formation and inhibited renal fibrosis and inflammation, whereas NETs adoptive transfer exacerbated the fibrotic process. Moreover, NET-mediated renal fibrosis was associated with enhanced infiltration of cytotoxic CD8⁺ T cells, which produced granzyme B (GZMB) to drive tubular cell epithelial-mesenchymal transition (EMT) and fibroblast activation. Accordingly, pharmacological inhibition of GZMB resulted in blunted kidney inflammation and fibrosis. Furthermore, NETs profoundly potentiated the production of T-cell chemokines CXCL9/10/11 in macrophages, but not in tubular cells or fibroblasts, thus driving T-cell infiltration and fueling inflammatory cascades in the kidneys. Mechanistically, the NET-macrophage interaction was partially mediated by the TLR2/4 signaling. Thus, our work reveals a previously unexplored role of the collaboration between NETs and macrophages in supporting CD8⁺ T cell infiltration, which orchestrates kidney inflammation and fibrosis.

The entorhinal cortex (EC)-hippocampal (HPC) circuit is particularly vulnerable to Alzheimer's disease (AD) pathology, yet the underlying molecular mechanisms remain unclear. By employing the high-depth sequencing strategy Smart-seq2, we tracked gene expression changes across various neuron types within this circuit at different stages of AD pathology. We observed a decrease in the extent of gene expression changes in AD versus wild-type (WT) mice as the disease advanced. Functionally, we demonstrate that both mitochondrial and ribosomal pathways were increasingly activated, while neuronal pathways were inhibited with AD progression. Our findings indicate that the reduction of EC-stellate cells disrupts Meg3-mediated energy metabolism, contributing to energy dysfunction in AD. Additionally, we identified GFAP-positive neurons as a distinct population of disease-associated neurons, exhibiting a loss of neuronal-like characteristics, alongside the emergence of glia- and stem-like features. The number of GFAP-positive neurons increased with AD progression, a trend consistently observed in both AD model mice and AD patients. In summary, this study identifies and characterizes GFAP-positive neurons as a novel subtype of disease-associated neurons in AD pathology, providing insights into their potential role in disease progression.