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<p>Liver fibrosis remains a significant clinical challenge with limited therapeutic options. Apoptotic extracellular vesicles (apoVs) derived from macrophages have emerged as promising mediators of tissue repair, but their role in shaping liver fibrosis is poorly understood. Here, we demonstrate that M2 macrophage-derived apoVs (M2-apoVs) alleviate liver fibrosis by modulating hepatic stellate cells (HSCs) activation. Mechanistically, M2-apoVs deliver miR-1224-5p to HSCs, which suppresses the SP1/TGF-β pathway, thereby inhibiting fibrogenic gene expression, proliferation, and migration. In vitro, M2-apoVs reduced extracellular matrix (ECM) deposition by downregulating the expression of collagen I (Col I) and α-smooth muscle actin (α-SMA) in HSCs. Furthermore, M2-apoVs promoted the establishment of an antifibrotic microenvironment by regulating macrophage polarization and HSC-macrophage crosstalk. In a CCl₄-induced liver fibrosis mouse model, M2-apoVs treatment significantly reduced collagen accumulation and improved liver histology. Our findings revealed a novel miR-1224-5p/SP1/TGF-β regulatory axis in liver fibrosis and highlighted the therapeutic potential of M2-apoVs as a cell-free strategy for treating fibrotic liver diseases.</p> Graphical Abstract <p></p>

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M2 macrophage-derived apoptotic vesicles alleviate liver fibrosis via miR-1224-5p-mediated inhibition of the SP1/TGF-β pathway in hepatic stellate cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月19日

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  • Ya Zhang,
  • Jin Lei,
  • Wanhang Deng,
  • Zhipeng Liang,
  • Tao Ran,
  • Huayue Wu,
  • Lu Han,
  • Xu Xu,
  • Qingxiu Zhang,
  • Jian Zhu,
  • Weiwen Yang,
  • Xueke Zhao

摘要

Liver fibrosis remains a significant clinical challenge with limited therapeutic options. Apoptotic extracellular vesicles (apoVs) derived from macrophages have emerged as promising mediators of tissue repair, but their role in shaping liver fibrosis is poorly understood. Here, we demonstrate that M2 macrophage-derived apoVs (M2-apoVs) alleviate liver fibrosis by modulating hepatic stellate cells (HSCs) activation. Mechanistically, M2-apoVs deliver miR-1224-5p to HSCs, which suppresses the SP1/TGF-β pathway, thereby inhibiting fibrogenic gene expression, proliferation, and migration. In vitro, M2-apoVs reduced extracellular matrix (ECM) deposition by downregulating the expression of collagen I (Col I) and α-smooth muscle actin (α-SMA) in HSCs. Furthermore, M2-apoVs promoted the establishment of an antifibrotic microenvironment by regulating macrophage polarization and HSC-macrophage crosstalk. In a CCl₄-induced liver fibrosis mouse model, M2-apoVs treatment significantly reduced collagen accumulation and improved liver histology. Our findings revealed a novel miR-1224-5p/SP1/TGF-β regulatory axis in liver fibrosis and highlighted the therapeutic potential of M2-apoVs as a cell-free strategy for treating fibrotic liver diseases.

Graphical Abstract