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<p>Fibrosis resulting from metabolic-associated steatohepatitis (MASH) is increasingly recognized as the predominant form of liver fibrosis. Although the activation of hepatic stellate cells (HSCs) is essential for liver fibrosis, the mechanisms underlying HSC activation in MASH remain inadequately understood. Integrated analysis of large-scale single-cell and single-nucleus RNA sequencing data from human healthy and fibrosis samples reveals a distinct subpopulation of HSCs in MASH. <i>AREL1</i> is a characteristic gene of this subpopulation and is uniquely upregulated in MASH-related fibrosis. HSC-specific knockout of <i>Arel1</i> markedly attenuates liver fibrosis in MASH model male mice. Mechanistically, <i>AREL1</i> is regulated by cholesterol and facilitates HSC activation through the <i>AREL1</i>-<i>ILK</i> axis, subsequently activating the PI3K-AKT signaling pathway. Moreover, therapeutic knockdown of <i>Arel1</i> using vitamin A-modified lipid nanoparticles markedly ameliorates MASH-related liver fibrosis. Here, we show a unique mechanism underlying HSC activation in MASH-driven fibrosis and present the targeted knockdown of <i>AREL1</i> in HSCs as a therapeutic avenue.</p>

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Therapeutic targeting of AREL1 in hepatic stellate cells attenuates MASH-related liver fibrosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月21日

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  • Yang-Wen-Qing Zhang,
  • Xiaoyu Pan,
  • Minghe Zhang,
  • Junyu Zhang,
  • Hui Ren,
  • Xinyu Zong,
  • Xiaomian Li,
  • Kequan Xu,
  • Peng Xia,
  • Tiangen Wu,
  • Weijie Ma,
  • Xi Chen,
  • Chengming Qu,
  • Wenzhi He,
  • Yufeng Yuan

摘要

Fibrosis resulting from metabolic-associated steatohepatitis (MASH) is increasingly recognized as the predominant form of liver fibrosis. Although the activation of hepatic stellate cells (HSCs) is essential for liver fibrosis, the mechanisms underlying HSC activation in MASH remain inadequately understood. Integrated analysis of large-scale single-cell and single-nucleus RNA sequencing data from human healthy and fibrosis samples reveals a distinct subpopulation of HSCs in MASH. AREL1 is a characteristic gene of this subpopulation and is uniquely upregulated in MASH-related fibrosis. HSC-specific knockout of Arel1 markedly attenuates liver fibrosis in MASH model male mice. Mechanistically, AREL1 is regulated by cholesterol and facilitates HSC activation through the AREL1-ILK axis, subsequently activating the PI3K-AKT signaling pathway. Moreover, therapeutic knockdown of Arel1 using vitamin A-modified lipid nanoparticles markedly ameliorates MASH-related liver fibrosis. Here, we show a unique mechanism underlying HSC activation in MASH-driven fibrosis and present the targeted knockdown of AREL1 in HSCs as a therapeutic avenue.