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

• Published in: Journal of translational medicine Vol. 23; no. 1; pp. 810 - 15
• Main Authors: Zhao, Fangqing, Niu, Xuan, Song, Ge, Wang, Lijie, Fu, Yisheng, Li, Shuwen, Gu, Xinxin, Wang, Qingkun, Luo, Jiao
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 22.07.2025; BioMed Central; BMC
• Subjects: AAV; Animals; Base Sequence; Cell Line; Cell Proliferation; Down-Regulation - genetics; Fatty Liver - complications; Fatty Liver - genetics; Fatty Liver - pathology; Fibrosis; Gene expression; Gene Expression Regulation; Gene therapy; Genes; 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; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; MiR-214; Physiological aspects; China; Hepatic stellate cell; Liver fibrosis; MiR-214; Gene therapy; AAV
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-025-06880-x

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. 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. 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. 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.