Key Takeaways & Executive Findings
- •• YGJ preconditioning enhances the anti-fibrotic cargo of BMSC-EVs, specifically upregulating miR-7045-5p. • YGJ-EVs deliver miR-7045-5p to hepatic stellate cells, inhibiting the Akt/AMPK/TFEB pathway and promoting lysosomal biogenesis and mitophagy. • In a CCl4-induced mouse model, YGJ-EVs ameliorate liver fibrosis and improve hepatic function, highlighting their therapeutic potential. • miR-7045-5p overexpression alone attenuates TGF-β1-induced HSC activation, confirming its causative role in the anti-fibrotic effect.
Abstract
Background Liver fibrosis is a crucial pathological stage in the progression of chronic liver diseases. Yiguanjian (YGJ), a Chinese herbal formula, exhibits anti-inflammatory, anti-fibrotic, and hepatoprotective effects. Extracellular vesicles from bone-marrow mesenchymal stem cells (BMSC-EVs) have shown potential in treating various disorders, including liver fibrosis. This study investigated the regulatory effects of EVs from YGJ-preconditioned BMSCs (YGJ-EVs) on TGF-β1-stimulated hepatic stellate cells (HSCs) and their therapeutic potential in a mouse model of liver fibrosis, with a focus on identifying the causative microRNA cargo. Methods YGJ-EVs and control EVs were isolated from BMSC culture supernatants and characterized via western blotting, transmission electron microscopy, and nanoparticle tracking analysis. Their cellular uptake in vitro and in vivo was evaluated using DIR labeling. To identify candidate miRNAs mediating YGJ-EV bioactivity, miRNA microarray analysis was conducted. To assess the effect of YGJ-EVs on liver fibrosis, TGF-β1-activated HSC cells were treated with YGJ-EVs or control-EVs for 24 h, and then the expression of proteins related to fibrotic activation (COL1-A1 and α-SMA), lysosomal biogenesis (LAMP1, TPP1, CTSD, and CTSB) mitophagy (p62, LC3, PINK1, and Parkin), and the Akt/AMPK/TFEB pathway was assessed. To determine whether miR-7045-5p is the causative factor, HSC cells transfected with miR-7045-5p were similarly analyzed. Results miRNA microarray analysis revealed miR-7045-5p upregulation in YGJ-EVs versus control EVs. In CCl4-treated mice, YGJ-EV-derived miR-7045-5p ameliorated the liver fibrosis, improved the hepatic function, and suppressed the HSC activation by inhibiting the Akt/AMPK/TFEB pathway. In vitro, miR-7045-5p overexpression attenuated TGF-β1-induced HSC activation. Conclusion YGJ increases miR-7045-5p abundance in BMSC-EVs. YGJ-EVs alleviate liver fibrosis by delivering the anti-fibrotic miRNA miR-7045-5p, which inhibits the Akt/AMPK/TFEB pathway, thereby promoting lysosomal biogenesis and mitophagy in HSCs.
1. Introduction
Chronic liver disease poses a major global health burden, accounting for approximately 2 million deaths annually worldwide [1]. Hepatic fibrosis is a common pathological feature of chronic liver diseases. It is characterized by the progressive accumulation and deposition of excessive extracellular matrix (ECM). When ECM synthesis surpasses ECM degradation, hepatic fibrosis may progress to cirrhosis and ultimately develop into hepatocellular carcinoma [2]. The degree of fibrosis directly influences both the quality of life and survival outcomes of patients with liver disease [3]. Despite extensive research, the underlying mechanisms of hepatic fibrosis remain incompletely understood, and effective diagnostic and therapeutic options are still lacking. Therefore, continued investigation into strategies for alleviating hepatic fibrosis remains of significant clinical importance.
Mesenchymal stem cell (MSC)-based regenerative therapy is a clinical approach in which MSCs contribute to liver regeneration either directly, by migrating to hepatic tissue, or indirectly, via their paracrine secretome [4]. This strategy has emerged as a highly promising therapeutic option for liver diseases, although potential risks such as immune rejection and tumorigenesis remain [5]. Bone-marrow-MSC-derived extracellular vesicles (BMSC-EVs), nanoscale vesicles measuring 40–160 nm in diameter, are enriched with functional proteins, mRNAs, and microRNAs (miRNAs). As key mediators of intercellular communication, BMSC-EVs exert diverse regulatory effects on target cells [6]. Studies have demonstrated that BMSC-EVs suppress hepatic stellate cell (HSC) activation and collagen deposition [7]. Moreover, pretreatment of MSCs with cytokines or small-molecule compounds can enhance their therapeutic efficacy [8, 9]. For instance, BMSC-EVs preconditioned with baicalin demonstrate improved inhibition of the JAK2/STAT3 pathway and correction of Th17/Treg cell imbalance, thereby alleviating hepatic ischemia-reperfusion injury [10].
Yiguanjian (YGJ), a traditional Chinese medicine (TCM) formula composed of Rehma...
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Zhejun Liu, Xiaodan Jiang, Hongjie You, Zuoqing Tang, Yun Ma, Niancong Che, Chongyang Ma, Wenlan Liu (2026). Extracellular vesicles from Yiguanjian-primed bone-marrow mesenchymal stem cells ameliorate chronic liver fibrosis via miR-7045-5p. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04780-x
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Frequently Asked Questions
What is the role of miR-7045-5p in liver fibrosis?
miR-7045-5p is an anti-fibrotic microRNA that inhibits hepatic stellate cell activation by suppressing the Akt/AMPK/TFEB pathway, thereby promoting lysosomal biogenesis and mitophagy.
How do Yiguanjian-preconditioned BMSC-EVs alleviate liver fibrosis?
YGJ-EVs deliver miR-7045-5p to hepatic stellate cells, which inhibits the Akt/AMPK/TFEB pathway, leading to reduced fibrotic activation and improved liver function in a mouse model.
What is the significance of Yiguanjian in this study?
Yiguanjian is a Chinese herbal formula that enhances the therapeutic efficacy of BMSC-EVs by increasing the abundance of miR-7045-5p, thereby improving their anti-fibrotic properties.
What methods were used to identify the causative miRNA?
miRNA microarray analysis was performed on YGJ-EVs and control EVs, revealing upregulation of miR-7045-5p. Subsequent in vitro and in vivo experiments confirmed its role.
What are the potential clinical implications of this research?
This study suggests that YGJ-EVs could be developed as a novel cell-free therapy for liver fibrosis, offering a safer and more effective alternative to direct MSC transplantation.
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