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Cited by 27Extracellular vesicles in diseaseMesenchymal stem cell researchLiver physiology and pathology

Exosomal miR-499a-5p from human umbilical cord mesenchymal stem cells attenuates liver fibrosis via targeting ETS1/GPX4-mediated ferroptosis in hepatic stellate cells

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Wang, Zheng, Yuan, Mengqin, Yao, Lichao, Xiong, Zhiyu, Dai, Kai, Liu, Pingji, Chen, Ping, Sun, Muhua +3 more·2025·Journal of Nanobiotechnology
DOI 10.1186/s12951-025-03291-4PMC PMC11921658
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Abstract

Liver fibrosis is a leading cause of liver-related mortality worldwide, yet effective therapies remain limited. Mesenchymal stem cells (MSCs) have recently shown promise in treating liver fibrosis due to their anti-inflammatory and anti-fibrotic properties. However, the precise molecular mechanisms by which MSCs exert their effects remain unclear. In this study, we explored how human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) contribute to treating liver fibrosis, and revealed a crucial role of ferroptosis in modulating hepatic stellate cells (HSCs) activity. We found that MSCs primarily promote ferroptosis in HSCs in an exosome-dependent manner. Specifically, MSC-derived exosomes (MSC-Exos) deliver miR-499a-5p, which interacts with the transcription factor ETS1, leading to the suppression of GPX4, a key regulator of ferroptosis, thereby reducing the fibrogenic activity of HSCs. Overexpression of ETS1 in HSCs counteracted miR-499a-5p-induced ferroptosis, underscoring the pathway's potential as a target for therapeutic intervention. Furthermore, molecular docking simulations further identified optimal ETS1-GPX4 binding sites. This research uncovers a novel mechanism by which MSCs may treat liver fibrosis, providing insights that could guide the development of more effective therapies for this widespread condition.

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Cited by

Sorted by citations

Authors
Wang, Z., Yuan, M., Yao, L., Xiong, Z., Dai, K., Liu, P., Chen, P., Sun, M., Shu, K., Xia, Y., & Jiang, Y.
Affiliations
  • Renmin Hospital of Wuhan University (CN)
  • Wuhan Union Hospital (CN)
  • Wuhan University (CN)
Corresponding author
  • Xia, Yuchen
  • Jiang, Yingan
ORCID
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2025-03-19
Volume
23
Issue
1
Pages
222-222
ISSN
1477-3155 (ISSN-L)
DOI
10.1186/s12951-025-03291-4
PMC
PMC11921658
OpenAlex
W4408635707
Cited by
27
References
6
Citations by year
2026: 18 · 2025: 9
FWCI
8.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Nanobiotechnology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • the Anti-aging Research Center of Wuhan University Education Development Foundation (2002330)
  • the National Stem Cell Clinical Research Project of China
  • National Natural Science Foundation of China (81972673)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
liver fibrosis, human umbilical cord mesenchymal stem cells, exosomes, miR-499a-5p, ETS1, GPX4, ferroptosis, hepatic stellate cells
MeSH terms
Ferroptosis, Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Humans, Liver Cirrhosis, Umbilical Cord, MicroRNAs, Proto-Oncogene Protein c-ets-1, Mice, Hepatic Stellate Cells, Exosomes, Mesenchymal Stem Cells, Molecular Docking Simulation

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