Abstract

Liver fibrosis commences with liver injury stimulating transforming growth factor beta (TGFβ) activation of hepatic stellate cells (HSCs), causing scarring and irreversible damage. TGFβ induces expression of the transcription factor Forkhead box S1 (FOXS1) in hepatocytes and may have a role in the pathogenesis of hepatocellular carcinoma (HCC). To date, no studies have determined how it affects HSCs. We analyzed human livers with cirrhosis, HCC, and a murine fibrosis model and found that FOXS1 expression is significantly higher in fibrotic livers but not in HCC. Next, we treated human LX2 HSC cells with TGFβ to activate fibrotic pathways, and FOXS1 mRNA was significantly increased. To study TGFβ-FOXS1 signaling, we developed human LX2 FOXS1 CRISPR KO and scrambled control HSCs. To determine differentially expressed gene transcripts controlled by TGFβ-FOXS1, we performed RNA-seq in the FOXS1 KO and control cells and over 400 gene responses were attenuated in the FOXS1 KO HSCs with TGFβ- activation. To validate the RNA-seq findings, we used our state- of-the-art PamGene PamStation kinase activity technology that measures hundreds of signaling pathways nonselectively in real time. Using our RNA-seq data, kinase activity data, and descriptive measurements, we found that FOXS1 controls pathways mediating TGFβ responsiveness, protein translation, and proliferation. Our study is the first to identify that FOXS1 may serve as a biomarker for liver fibrosis and HSC activation, which may help with early detection of hepatic fibrosis or treatment options for end-stage liver disease.

Document Type

Article

Publication Date

2024

Notes/Citation Information

© 2024 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Funding Information

This work was not supported by grant funding. However, author salaries were supported by grants during the studies from the National Institutes of Health (NIH) R01DK121797 (T. D. H. J.), R01DA058933 (T. D. H. J.), K01DK128022 (R. N. H.) and F31HL170972 (Z. A. K.), as well as the American Heart Association (23CDA1051959) and University of Toledo Foundation (J. F. C.). NIH grants P50AA024333 and P30CA177558 supported the mouse and human HCC samples, respectively. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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