Abstract
Increasing evidence has demonstrated that excessive fructose intake induces liver fibrosis. Epithelial–mesenchymal transition (EMT) driven by transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (Smad) signaling activation promotes the occurrence and development of liver fibrosis. Magnesium isoglycyrrhizinate is clinically used as a hepatoprotective agent to treat liver fibrosis, but its underlying molecular mechanism has not been identified. Using a rat model, we found that high fructose intake reduced microRNA (miR)-375-3p expression and activated the janus-activating kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) cascade and TGF-β1/Smad signaling, which is consistent with the EMT and liver fibrosis. To further verify these observations, BRL-3A cells and/or primary rat hepatocytes were exposed to high fructose and/or transfected with a miR-375-3p mimic or inhibitor or treated with a JAK2 inhibitor, and we found that the low expression of miR-375-3p could induce the JAK2/STAT3 pathway to activate TGF-β1/Smad signaling and promote the EMT. Magnesium isoglycyrrhizinate was found to ameliorate high fructose-induced EMT and liver fibrosis in rats. More importantly, magnesium isoglycyrrhizinate increased miR-375-3p expression to suppress the JAK2/STAT3 pathway and TGF-β1/Smad signaling in these animal and cell models. This study provides evidence showing that magnesium isoglycyrrhizinate attenuates liver fibrosis associated with a high fructose diet.
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Change history
07 September 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41401-021-00771-9
18 September 2025
A Correction to this paper has been published: https://doi.org/10.1038/s41401-025-01656-x
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Acknowledgements
This work was partially supported by the Natural Science Foundation of Jiangsu Province (Grant No. BK20141243).
Author contributions
Conducted the experiments: YZY, XJZ, YP. Contributed new reagents or analytic tools: YP, SCW and SJW. Performed the data analysis: YZY, XJZ, LDK, QXU, HMG, and HJX. Wrote or contributed to the writing of the manuscript: LDK, YZY, QX, HJX, and RQJ. Participated in the research design: LDK and HMG
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Yang, Yz., Zhao, Xj., Xu, Hj. et al. Magnesium isoglycyrrhizinate ameliorates high fructose-induced liver fibrosis in rat by increasing miR-375-3p to suppress JAK2/STAT3 pathway and TGF-β1/Smad signaling. Acta Pharmacol Sin 40, 879–894 (2019). https://doi.org/10.1038/s41401-018-0194-4
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DOI: https://doi.org/10.1038/s41401-018-0194-4
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