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Background <p>Acute liver failure (ALF) is a life-threatening clinical syndrome characterized by massive hepatocyte death and insufficient regenerative response. However, the epigenetic mechanisms that disturb the balance between cell death and regeneration remain largely unclear.</p> Materials and methods <p>We integrated transcriptomic data from public ALF patient cohorts, a CCl₄-induced murine ALF model, and an APAP-induced murine ALF model. Bioinformatic analyses included single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA). The functional role of EZH1 was validated using EZH1 knockout mice, and liver injury was evaluated by serum biochemistry, histopathology, and immunohistochemistry.</p> Results <p>Integrated transcriptomic analysis revealed concurrent activation of apoptotic and proliferative pathways in ALF <i>(</i><i>P</i> &lt; 0.001). WGCNA identified EZH1 as a key hub gene strongly correlated with both apoptosis and proliferation (cor &gt; 0.5, <i>P</i> &lt; 0.001). Patients with low EZH1 expression exhibited significantly reduced apoptotic signaling (<i>P</i> &lt; 0.05) and enhanced regenerative signatures (<i>P</i> &lt; 0.001). In vivo, Ezh1 knockout markedly alleviated liver injury, as indicated by reduced serum ALT and AST levels (<i>P</i> &lt; 0.01), decreased levels of GSH (<i>P</i> &lt; 0.05) and MDA (<i>P</i> &lt; 0.01), and fewer TUNEL-positive apoptotic cells (<i>P</i> &lt; 0.01), accompanied by increased Ki67- (<i>P</i> &lt; 0.01) and PCNA-positive cells (<i>P</i> &lt; 0.05).</p> Conclusions <p>Our findings identify EZH1 as a pivotal epigenetic regulator promoting hepatocyte apoptosis in ALF. Targeted inhibition of EZH1 may offer a promising therapeutic approach to restore the balance between hepatocyte death and regeneration, thereby facilitating liver repair.</p>

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EZH1 Inhibition attenuates apoptosis and promotes regeneration for liver repair in acute liver failure

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月24日

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  • Ying You,
  • Feng Gu,
  • Meihua Mei,
  • Ningxin Tan,
  • Xiao Cong,
  • Peidong Chi,
  • Yili Chen,
  • Junqi Huang

摘要

Background

Acute liver failure (ALF) is a life-threatening clinical syndrome characterized by massive hepatocyte death and insufficient regenerative response. However, the epigenetic mechanisms that disturb the balance between cell death and regeneration remain largely unclear.

Materials and methods

We integrated transcriptomic data from public ALF patient cohorts, a CCl₄-induced murine ALF model, and an APAP-induced murine ALF model. Bioinformatic analyses included single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA). The functional role of EZH1 was validated using EZH1 knockout mice, and liver injury was evaluated by serum biochemistry, histopathology, and immunohistochemistry.

Results

Integrated transcriptomic analysis revealed concurrent activation of apoptotic and proliferative pathways in ALF (P < 0.001). WGCNA identified EZH1 as a key hub gene strongly correlated with both apoptosis and proliferation (cor > 0.5, P < 0.001). Patients with low EZH1 expression exhibited significantly reduced apoptotic signaling (P < 0.05) and enhanced regenerative signatures (P < 0.001). In vivo, Ezh1 knockout markedly alleviated liver injury, as indicated by reduced serum ALT and AST levels (P < 0.01), decreased levels of GSH (P < 0.05) and MDA (P < 0.01), and fewer TUNEL-positive apoptotic cells (P < 0.01), accompanied by increased Ki67- (P < 0.01) and PCNA-positive cells (P < 0.05).

Conclusions

Our findings identify EZH1 as a pivotal epigenetic regulator promoting hepatocyte apoptosis in ALF. Targeted inhibition of EZH1 may offer a promising therapeutic approach to restore the balance between hepatocyte death and regeneration, thereby facilitating liver repair.