Goosecoid promotes hepatic stellate cell epithelial-mesenchymal transition via transcriptional activation of serum- and glucocorticoid-induced protein kinase 1 in liver fibrosis.

Abstract

BACKGROUND: Goosecoid (GSC) is a transcription factor implicated in epithelial-mesenchymal transition (EMT) during embryogenesis and cancer, but its function in organ fibrosis remains poorly understood. This study investigates the role and mechanistic targets of GSC in hepatic stellate cell (HSC) EMT during liver fibrogenesis. METHODS: We analyzed GSC and EMT marker expression in primary HSCs isolated from murine liver fibrosis models induced by carbon tetrachloride (CCl₄) or bile duct ligation (BDL), and in TGF-β-stimulated LX-2 cells. The functional role of GSC was validated via in vitro and in vivo GSC knockdown, while chromatin immunoprecipitation sequencing (ChIP-seq) combined with experimental verification was used to identify its target genes and regulatory mechanisms. RESULTS: GSC expression was significantly upregulated in activated HSCs from fibrotic mouse models and TGF-β-induced LX-2 cells, which was closely associated with enhanced EMT (downregulation of epithelial markers, upregulation of mesenchymal markers). Functional assays confirmed that GSC knockdown suppressed HSC EMT in vitro and ameliorated liver fibrosis in vivo via AAV-mediated HSC-specific GSC silencing. Mechanistically, we found that GSC undergoes increased nuclear translocation during HSC activation. ChIP-seq analysis identified Serum- and glucocorticoid-induced protein kinase 1 (SGK1) as a direct transcriptional target of GSC. Further validation revealed that SGK1, in turn, promotes HSC EMT by activating the NF-κB signaling pathway. CONCLUSION: This study uncovers a novel mechanism by which GSC promotes HSC EMT and liver fibrosis through direct transcriptional activation of SGK1, followed by downstream NF-κB pathway activation. SUMMARY: GSC is markedly upregulated in activated HSCs from murine fibrosis models (CCl₄/BDL) and during TGF-β-induced EMT. HSC-specific GSC knockdown attenuated liver fibrosis progression. Mechanistically, GSC translocates to the nucleus where it binds the SGK1 promoter to enhance transcription, subsequently driving HSC EMT and promoting fibrogenesis through the NF-κB signaling pathway.