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

Publisher: BioMed Central Country of Publication: England NLM ID: 101152208 Publication Model: Electronic Cited Medium: Internet ISSN: 1477-3155 (Electronic) Linking ISSN: 14773155 NLM ISO Abbreviation: J Nanobiotechnology Subsets: MEDLINE

Original Publication: London : BioMed Central, 2003-

MicroRNAs*/metabolism ; MicroRNAs*/genetics ; Ferroptosis* ; Mesenchymal Stem Cells*/metabolism ; Mesenchymal Stem Cells*/cytology ; Liver Cirrhosis*/metabolism ; Liver Cirrhosis*/therapy ; Proto-Oncogene Protein c-ets-1*/metabolism ; Proto-Oncogene Protein c-ets-1*/genetics ; Exosomes*/metabolism ; Hepatic Stellate Cells*/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase*/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase*/genetics; Humans ; Umbilical Cord/cytology ; Molecular Docking Simulation ; Animals

Competing Interests: Declarations. Ethical approval: The animal study adhered to the guidelines set forth by the Declaration of Helsinki, and the research protocol received approval from the Animal Care and Use Committee at Renmin Hospital of Wuhan University (Approval Nos. 20220901 A, 20230103 C). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
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.
(© 2025. The Author(s).)

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2002330 the Anti-aging Research Center of Wuhan University Education Development Foundation; 81972673 National Natural Science Foundation of China

0 (MicroRNAs)
0 (Proto-Oncogene Protein c-ets-1)
0 (ETS1 protein, human)
EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
0 (MIRN499 microRNA, human)

Date Created: 20250320 Date Completed: 20250513 Latest Revision: 20250513

20250514

PMC11921658

10.1186/s12951-025-03291-4

40108627