Scholarlink

Objective <p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide, with the progression of its fibrosis serving as a critical determinant of patient prognosis. This study aims to elucidate the molecular mechanisms by which lipidotoxic hepatocyte-derived small extracellular vesicles (LTH-sEV) promote the activation of hepatic stellate cells (HSCs) and the progression of MASLD-associated liver fibrosis through the transport of fatty acid synthase (FASN).</p> Approach and results <p>The biological characteristics of LTH-sEV were characterized using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and western blot. In vitro experiments demonstrated that treatment with LTH-sEV significantly increased levels of reactive oxygen species (ROS), decreased glutathione (GSH) content, elevated malondialdehyde (MDA) levels, and upregulated the expression of α-smooth muscle actin (α-SMA) and collagen (COL1A1, COL3A1) in HSCs. Liquid chromatography-mass spectrometry (LC–MS) analysis identified significant enrichment of FASN protein in LTH-sEV. Gene editing experiments demonstrated that FASN overexpression exacerbated the pro-fibrotic effects of LTH-sEV, while FASN knockdown reversed these effects. Animal experiments revealed that LTH-sEV injection significantly increased the area of liver fibrosis in high-fat diet (HFD) mice, and FASN knockdown or inhibitor reversed the effects of LTH-sEV.</p> Conclusion <p>This study reveals the molecular mechanism through which LTH-sEV exacerbate oxidative stress in HSCs via FASN transport, providing a theoretical basis for developing anti-fibrotic strategies targeting the sEV-FASN axis. Future research could further explore the clinical translational value of FASN inhibition-based precision therapy in MASLD.</p> Graphical abstract <p>LTH-sEV transferred FASN into HSCs. FASN promotes HSC oxidative stress by increasing MDA and ROS levels and decreasing GSH levels, which results in HSC activation and aggravates MASLD fibrosis.</p> <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Small extracellular vesicles derived from lipotoxic hepatocytes transport FASN to promote hepatic stellate cell activation

  • 期刊论文

  • 发表日期：

    2025年11月12日

查看全文
  • Yujie Shi,
  • Lixian Yi,
  • Yifei Chen,
  • Fuji Yang,
  • Hai Qian,
  • Fatma A. Abouelnazar,
  • Yongmin Yan,
  • Yanjin Wang

摘要

Objective

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide, with the progression of its fibrosis serving as a critical determinant of patient prognosis. This study aims to elucidate the molecular mechanisms by which lipidotoxic hepatocyte-derived small extracellular vesicles (LTH-sEV) promote the activation of hepatic stellate cells (HSCs) and the progression of MASLD-associated liver fibrosis through the transport of fatty acid synthase (FASN).

Approach and results

The biological characteristics of LTH-sEV were characterized using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and western blot. In vitro experiments demonstrated that treatment with LTH-sEV significantly increased levels of reactive oxygen species (ROS), decreased glutathione (GSH) content, elevated malondialdehyde (MDA) levels, and upregulated the expression of α-smooth muscle actin (α-SMA) and collagen (COL1A1, COL3A1) in HSCs. Liquid chromatography-mass spectrometry (LC–MS) analysis identified significant enrichment of FASN protein in LTH-sEV. Gene editing experiments demonstrated that FASN overexpression exacerbated the pro-fibrotic effects of LTH-sEV, while FASN knockdown reversed these effects. Animal experiments revealed that LTH-sEV injection significantly increased the area of liver fibrosis in high-fat diet (HFD) mice, and FASN knockdown or inhibitor reversed the effects of LTH-sEV.

Conclusion

This study reveals the molecular mechanism through which LTH-sEV exacerbate oxidative stress in HSCs via FASN transport, providing a theoretical basis for developing anti-fibrotic strategies targeting the sEV-FASN axis. Future research could further explore the clinical translational value of FASN inhibition-based precision therapy in MASLD.

Graphical abstract

LTH-sEV transferred FASN into HSCs. FASN promotes HSC oxidative stress by increasing MDA and ROS levels and decreasing GSH levels, which results in HSC activation and aggravates MASLD fibrosis.