H19/miR‐148a/USP4 axis facilitates liver fibrosis by enhancing TGF‐β signaling in both hepatic stellate cells and hepatocytes

Liver fibrosis is a wound‐healing response represented by excessive extracellular matrix deposition. Activation of hepatic stellate cell (HSC) is the critical cellular basis for hepatic fibrogenesis, whereas hepatocyte undergoes epithelial‐mesenchymal transition (EMT) which is also involved in chronic liver injury. Long noncoding RNA H19 has been found to be associated with cholestatic liver fibrosis lately. However, the role of H19 in liver fibrosis remains largely to be elucidated. In this study, we found that the expression of H19 was significantly upregulated in the liver tissue of CCl4‐induced mice, a toxicant‐induced liver fibrogenesis model. Overexpression of H19 significantly aggravated activation of HSC and EMT of hepatocyte both by stimulating transforming growth factor‐β (TGF‐β) pathway. In terms of mechanism, H19 functioned as a competing endogenous RNA to sponge miR‐148a and subsequently sustained the level of ubiquitin‐specific protease 4 (USP4), which was an identified target of miR‐148a and was able to stabilize TGF‐β receptor I. In conclusion, our findings revealed a novel H19/miR‐148a/USP4 axis which promoted liver fibrosis via TGF‐β pathway in both HSC and hepatocyte, indicating that H19 could become a promising target for the treatment of liver fibrosis. H19/miR‐148a/ubiquitin‐specific protease 4 (USP4) axis promotes liver fibrosis by both activating hepatic stellate cell (HSC) and inducing epithelial‐mesenchymal transition (EMT) in hepatocyte. Overexpressing H19 elevated the levels of alpha‐smooth muscle actin (α‐SMA) in LX‐2 cells and EMT markers in L‐02 cells by antagonizing the suppressive effect of miR‐148a on USP4 and promoting transforming growth factor‐β (TGF‐β) pathway