Hepatic stellate cell-specific miR-214 expression alleviates liver fibrosis without boosting steatosis and inflammation

Background Liver fibrosis is a progressive pathological process primarily driven by the transdifferentiation of hepatic stellate cells (HSCs) into myofibroblast-like cells which secrete excessive extracellular matrix (ECM). Although microRNAs (miRNAs) have emerged as key regulators of fibrogenesis,...

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Veröffentlicht in:	Journal of translational medicine Jg. 23; H. 1; S. 810 - 15
Hauptverfasser:	Zhao, Fangqing, Niu, Xuan, Song, Ge, Wang, Lijie, Fu, Yisheng, Li, Shuwen, Gu, Xinxin, Wang, Qingkun, Luo, Jiao
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London BioMed Central 22.07.2025 BioMed Central Ltd BMC
Schlagworte:	AAV Animals Base Sequence Biomedical and Life Sciences Biomedicine Cell Line Cell Proliferation Down-Regulation - genetics Fatty Liver - complications Fatty Liver - genetics Fatty Liver - pathology Fibrosis Gene Expression Regulation Gene therapy Genetic aspects Health aspects Hepatic stellate cell Hepatic Stellate Cells - metabolism Hepatic Stellate Cells - pathology Humans Inflammation Inflammation - complications Inflammation - genetics Inflammation - pathology Liver cells Liver Cirrhosis - complications Liver Cirrhosis - genetics Liver Cirrhosis - pathology Liver diseases Liver fibrosis Male Medical research Medicine, Experimental Medicine/Public Health Mice Mice, Inbred C57BL MicroRNA MicroRNAs - genetics MicroRNAs - metabolism MiR-214 Physiological aspects China MiR-214 Hepatic stellate cell Liver fibrosis Gene therapy AAV
ISSN:	1479-5876, 1479-5876
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Zusammenfassung:	Background Liver fibrosis is a progressive pathological process primarily driven by the transdifferentiation of hepatic stellate cells (HSCs) into myofibroblast-like cells which secrete excessive extracellular matrix (ECM). Although microRNAs (miRNAs) have emerged as key regulators of fibrogenesis, the therapeutic potential and mechanistic specificity of miR-214-3p (miR-214) in liver fibrosis remain insufficiently defined. Methods An adeno-associated virus (AAV)-based system was used to achieve either whole-liver or HSC-specific overexpression of miR-214 (via GFAP promoter) in a mouse model of alcohol-associated liver fibrosis induced by Lieber-DeCarli ethanol diet combined with low-dose CCl₄ injection. Liver fibrosis, steatosis, and inflammation were evaluated by biochemical assays, histology, immunostaining, and gene expression analyses. In vitro, stable miR-214 overexpression and knockdown in LX-2 cells were performed to assess effects on HSC proliferation, transdifferentiation, and ECM gene expression. MECP2 was identified as a direct functional target of miR-214 by bioinformatics and luciferase reporter assays. Results miR-214 expression was significantly downregulated during HSC activation in vitro and in fibrotic livers. Whole-liver overexpression of miR-214 alleviated liver fibrosis but caused undesirable steatosis and inflammation. Notably, HSC-specific miR-214 overexpression ameliorated liver fibrosis without inducing these adverse effects. Functionally, miR-214 inhibited HSC proliferation and ECM gene expression, while its inhibition promoted this process. Mechanistically, miR-214 exerts its anti-fibrosis function at least in part by directing targeting MECP2 , a critical regulator for HSC activation. Conclusions These findings not only identify miR-214 as a promising antifibrotic agent, but also highlight the translational advantage of cell-specific miRNA delivery. HSC-targeted miR-214 gene therapy may offer a promising and safer approach for treating liver fibrosis.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1479-5876 1479-5876
DOI:	10.1186/s12967-025-06880-x