Nuclear Factor I-B Delays Liver Fibrosis by Inhibiting Chemokine Ligand 5 Transcription.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a significant contributor to liver fibrosis due to hepatic stellate cells (HSCs) activation. The anti-apoptotic gene Nuclear Factor I-B (NFIB) has been implicated in regulating cell proliferation and differentiation in the context of liver injury. However, its role in HSCs differentiation remains unclear. Our study reveals NFIB as the most markedly down-regulated transcription factor during HSCs activation, as evidenced by single-cell sequencing analysis of liver fibrosis. Clinical examination of liver tissues from MASH fibrosis patients corroborated diminished NFIB expression in HSCs across varying fibrosis stages. Using a murine model of liver fibrosis induced by a choline-deficient, amino acid-restricted high-fat diet (CDAHFD) and carbon tetrachloride (CCl) exposure, we observed reduced fibrosis levels following NFIB overexpression. Subsequent RNA sequencing elucidated the mechanism by which NFIB operates in liver fibrosis. Specifically, NFIB is found to directly interact with the promoter region of the chemokine C─C motif ligand 5 (CCL5), suppressing its expression and thereby mitigating liver fibrosis by inhibiting oxidative stress. These findings uncover a previously unrecognized role of the NFIB/CCL5 axis in liver fibrosis progression, presenting a novel therapeutic target for liver fibrosis management.