Function And Mechanism Of JunB In Regulating Hepatic Stellate Cell Activity,Proliferation And Differentiation In Liver Fibrosis

Background: Recurring liver injury leads to inflammation and fibrosis,triggering serious diseases such as liver cirrhosis.Hepatic stellate cell(HSC)activation and proliferation are key processes during liver fibrogenesis.JunB proto-oncogene(JunB),an AP-1 component,is involved in acute liver inflammation.However,its fundamental cellular and molecular mechanisms in liver fibrosis remain unclear.Methods: Immunohistochemical,WB and RT-qPCR assays were used to evaluate JunB expression in human and mouse liver fibrotic tissues.Adenovirus-mediated sh RNA transfer to an early mouse liver fibrosis model was conducted to reveal the function of JunB in vivo;si RNA-mediated knockdown was used to identify its cellular and molecular mechanisms in vitro.RNA sequencing,immunofluorescence,and chromatin immunoprecipitation assays detected altered gene expression upon JunB knockdown.Results: We found that JunB levels were significantly increased in activated HSCs and positively correlated with liver fibrosis in human samples and in mice.Furthermore,knockdown of JunB in vivo attenuated CCl4-liver fibrosis,as indicated by decreased injury scores,inflammation and extracellular matrix.Mechanistically,the increase in JunB production was attributed to the activation of TGF-β1/p38 MAPK signaling pathway.Moreover,molecular biological experiments revealed that JunB binds to the epidermal growth factor receptor(EGFR)promoter region,thus promoting its transcription and subsequently upregulating its protein levels in activated HSCs.Conclusion: This study identifies JunB-mediated EGFR transcription is essential for TGF-β-dependent activation and proliferation of HSCs during liver fibrogenesis,suggesting JunB may be a coordinator between TGF-β1 and EGF signaling and a potential therapeutic target for liver fibrosis.