Bibliographic Details
| Title: |
Breaking the synergism of iron overload and miR-122 to rescue lipid accumulation and peroxidation in MASLD |
| Authors: |
Yuxiao Tang, Zelong Gao, Jianxin Yang, Chenqi Li, Weili Wang, Chenghua Wu, Mengpu Wu, Min Li, Huiwen Wu, Yan Sun, Hongwei Zhang, Yifeng Chai, Feng Xie, Jianxin Qian, Hui Shen, Dongyao Wang |
| Source: |
Pharmacological Research, Vol 215, Iss , Pp 107728- (2025) |
| Publisher Information: |
Elsevier, 2025. |
| Publication Year: |
2025 |
| Collection: |
LCC:Therapeutics. Pharmacology |
| Subject Terms: |
MASLD, MiR-122, Iron overload, Lipid peroxidation, Polyunsaturated fatty acids, Therapeutics. Pharmacology, RM1-950 |
| More Details: |
MASLD is a multifactorial disease with specific subtypes being featured by hepatic iron overload and loss of miR-122, a liver-specific microRNA regulating hepatic lipid homeostasis. Previously we reported the mechanism of iron overload decreasing miR-122. Interestingly, we found that mice lacking miR-122 were highly sensitive to iron overload-induced steatosis and fibrosis. The present study aimed to disclose the downstream mechanisms and the preventive measures targeting miR-122. We first validated the decreases in iron-related genes and miR-122 in MASLD. By using LC-MS/MS and gas-chromatography, we found that the combination of miR-122 knockout and iron overload significantly increased the production and peroxidation of polyunsaturated fatty acids (PUFAs). However, miR-122 knockout itself only incurred lipid accumulation, suggesting a synergistic effect of miR-122 knockout and iron overload in lipid peroxidation. We then located the key enzymes involved in PUFA production and peroxidation by the transcriptome and proteome analysis. Mechanistically, miR-122 and iron regulated fatty acid synthesis through Aacs, fatty acid desaturation through Fads2, and PUFAs oxidation through CYPs. Re-supplementation of miR-122 by recombinant adeno-associated virus or agomir effectively broke the synergism of miR-122 knockout and iron overload in vivo. We further designed a miR-122 expression reporter cell model for high-throughput screening on 2543 natural compounds, and eventually found and validated that the dihydroberberine could upregulate miR-122 expression and correct iron overload-induced lipid disorders. These results identified the synergistic role of miR-122 and iron in PUFAs production and peroxidation, and also proposed the potential application of dihydroberberine as a preventive and therapeutic candidate for MASLD. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1096-1186 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S1043661825001537; https://doaj.org/toc/1096-1186 |
| DOI: |
10.1016/j.phrs.2025.107728 |
| Access URL: |
https://doaj.org/article/d2ce5d494538465e9f8994ca6740d645 |
| Accession Number: |
edsdoj.2ce5d494538465e9f8994ca6740d645 |
| Database: |
Directory of Open Access Journals |
