Ubiquitin specific peptidase 1 promotes hepatic fibrosis through positive regulation of CXCL1 by deubiquitinating SNAIL

Abstract

BackgroundHepatic fibrosis is attributed to an imbalance of extracellular matrix production and lysis. Human hepatic stellate cells (HSCs) have been uncovered to converge through complex interactions with hepatocytes and immune cells, causing scarring in liver damage. AimsWe aimed to investigate the expression status of ubiquitin specific peptidase 1 (USP1) and its potential mechanisms on HSCs and hepatic fibrosis. MethodsHepatic fibrosis animal and cell models were generated using mice with carbon tetrachloride (CCl4) treatment and HSCs LX-2 with TGF-β1 treatment. Relationships among USP1, SNAIL, and CXCL1 were identified via dual-luciferase reporter gene assay, co-immunoprecipitation, and chromatin immunoprecipitation. With gain- and loss-of-experiments, CCK-8 and flow cytometry assays were employed for cell proliferation and apoptosis. ResultsUSP1 upregulated SNAIL expression through deubiquitination to increase CXCL1 expression. USP1 downregulation decreased expressions of fibrosis-related genes, suppressed proliferation, and promoted apoptosis in TGF-β1-induced LX-2 cells, which were reversed by SNAIL overexpression. The pro-fibrosis role caused by SNAIL upregulation was abolished by CXCL1 reduction. Promotive function of USP1/SNAIL/CXCL1 axis in hepatic fibrosis was further confirmed in vivo. ConclusionThese data supported siRNA-mediated silencing of USP1 improved hepatic fibrosis through inhibition of SNAIL and CXCL1, which yields a new therapeutic target for hepatic fibrosis treatment.