Abstract
BackgroundLiver fibrosis develops from various chronic liver diseases, and there is currently a lack of specific treatment strategies. Yiqi Rougan decoction (YQRG) is a traditional Chinese medicine that has shown durative effects in the treatment of liver fibrosis; however, the mechanism associated with YQRG-related improvements in liver fibrosis remains to be experimentally determined. This study evaluated the therapeutic effect of YQRG on carbon tetrachloride (CCl4)-induced liver fibrosis in rats and its molecular mechanism.MethodsWe used low-, medium-, and high-dose YQRG to treat CCl4-induced liver fibrosis in rats, followed by assessment of liver injury and fibrosis according to liver appearance, body weight, liver mass index, histopathologic examination, and serum testing. Additionally, we performed transcriptome analysis using RNA-sequencing (RNA-seq) technology, including cluster, Gene Ontology (GO), and pathway analyses, to identify differentially expressed genes (DEGs), and protein and gene expression were detected by immunofluorescence (IFC), western blot and real-time quantitative PCR.ResultsThe results showed that YQRG effectively alleviated CCl4-induced liver injury and fibrosis in rats, including observations of improved liver function, decreased activity of hepatic stellate cells (HSCs), and decreased extracellular matrix (ECM) deposition. Moreover, we identified downregulated and upregulated DEGs in the model group relative to the control and YQRG-treated groups, with GO analysis revealing their enrichment in biological processes, such as endoplasmic reticulum stress (ERS), apoptosis, and autophagy. Furthermore, pathway analysis showed that YQRG treatment downregulated the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/Akt (PI3K/AKT) signalling pathways and upregulated other signalling pathways, including those related to peroxisome proliferator-activated receptors(PPAR) and AMP-activated protein kinase(AMPK), with these findings subsequently verified experimentally.ConclusionThese findings showed that YQRG improved CCl4-induced liver fibrosis through multiple mechanisms and pathways, offering critical insight into the YQRG-related therapeutic mechanism and promoting further research into its potential application.
Highlights
Liver fibrosis develops from various chronic liver diseases, and there is currently a lack of specific treatment strategies
Yiqi Rougan decoction (YQRG) improves liver injury in vivo To evaluate the effect of YQRG on liver fibrosis, we established a rat model of liver fibrosis according to the reported protocol [22]
The liver weight ratio (LW: BW) used to evaluate liver injury showed that the LW: BW ratio decreased significantly in the YQRG treatment group (Fig. 2b)
Summary
Liver fibrosis develops from various chronic liver diseases, and there is currently a lack of specific treatment strategies. This study evaluated the therapeutic effect of YQRG on carbon tetrachloride (CCl4)-induced liver fibrosis in rats and its molecular mechanism. Actively reversing liver fibrosis is important to the prevention and treatment of chronic liver disease. Activation of resting hepatic stellate cells (HSCs) represents the critical mechanism associated with liver fibrosis formation [8,9,10]. Endoplasmic reticulum stress (ERS) describes the response to continuous aggregation of unfolded or misfolded proteins in the ER, which alters ER homeostasis [11], induces HPCs apoptosis, and reportedly promotes the formation of liver fibrosis [12, 13]. Recent studies show that continuous ERS can activate autophagy, which subsequently promotes the activation of resting HSCs and induces liver fibrosis [17, 18]
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