Exosomal miR-499a-5p from human umbilical cord mesenchymal stem cells attenuates liver fibrosis via targeting ETS1/GPX4-mediated ferroptosis in hepatic stellate cells
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 me...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-03-01
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| Series: | Journal of Nanobiotechnology |
| Online Access: | https://doi.org/10.1186/s12951-025-03291-4 |
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| Summary: | 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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| ISSN: | 1477-3155 |