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

  • Hepatol Int. 2025 Nov 12. doi: 10.1007/s12072-025-10953-w.
Yujie Shi  #  1  2  3 ,  Lixian Yi  #  4 ,  Yifei Chen  #  1  3 ,  Fuji Yang  1  3 ,  Hai Qian  3 ,  Fatma A Abouelnazar  5 ,  Yongmin Yan  6  7 ,  Yanjin Wang  8  9  10
Affiliations
  • 1. Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, 213017, China.
  • 2. Department of Laboratory Medicine, Hangzhou First People's Hospital Xiasha Campus, Hangzhou, China.
  • 3. Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
  • 4. School of Public Health, Suzhou Vocational Health College, Suzhou, China.
  • 5. Changzhou Key Laboratory of Exosome Foundation and Transformation Application, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, China.
  • 6. Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, 213017, China. [email protected].
  • 7. Changzhou Key Laboratory of Exosome Foundation and Transformation Application, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, China. [email protected].
  • 8. Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, 213017, China. [email protected].
  • 9. Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China. [email protected].
  • 10. Changzhou Key Laboratory of Exosome Foundation and Transformation Application, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou, 213017, China. [email protected].
  • # Contributed equally.
PMID: 41225085 DOI: 10.1007/s12072-025-10953-w
Abstract

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.

Keywords
FASN; HSC; LTH-sEV; MASLD.
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