Total glucosides of paeony inhibits liver fibrosis and inflammatory response associated with cirrhosis via the FLI1/NLRP3 axis

Background: Total glucosides of paeony (TGP) has a myriad of hepatoprotective activities. However, its role in cirrhosis, a major risk factor for hepatocellular carcinoma, remains largely unexplored. Here, we determined the impact of TGP on liver fibrosis and inflammation in mice modeled by carbon tetrachloride with an aim to explore a possible molecular mechanism. Methods: Liver fibrosis and inflammation in mice were evaluated using ELISA, hematoxylin-eosin, Masson's trichrome, immunohistochemical staining and TUNEL methods. The impact of TGP on gene expression in the liver tissues of the mice was investigated using microarray analysis, showing the most significant increase in expression of friend leukemia integration 1 transcription factor (FLI1). After loss-of-functions assays of FLI1, the downstream gene of FLI1 was searched by bioinformatics analysis and verified. Results: TGP reduced liver tissue damage, inhibited apoptosis, and alleviated liver fibrosis and inflammation in cirrhotic mice. FLI1 was downregulated in the liver of cirrhotic mice and lipopolysaccharide-treated hepatocytes, and TGP promoted the expression of FLI1. FLI1 depletion inhibited the effects of TGP on alleviating liver fibrosis and inflammatory responses in mice. FLI1 repressed Nod-like receptor protein 3 (NLRP3) transcription by binding to its promoter. Further silencing of NLRP3 in the presence of shFLI1 alleviated histopathological changes, inhibited apoptosis, and attenuated liver fibrosis and inflammatory responses in the liver of cirrhotic mice. Conclusions: TGP promotes the expression of FLI1, which in turn inhibits NLRP3 expression, thereby reducing cirrhosis-induced liver fibrosis and inflammatory response in mice.