2. Academic Validation
  3. Small extracellular vesicles derived from lipotoxic hepatocytes transport FASN to promote hepatic stellate cell activation

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

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.

Figures
Products