Liver-targeted degradation of BRD4 reverses hepatic fibrosis and enhances metabolism in murine models.

ABSTRACT: Background: Liver fibrosis, characterized by excessive extracellular matrix deposition, is a precursor to cirrhosis and hepatocellular carcinoma, and current treatments are often limited by off-target toxicities. Methods and results: We repurposed the liver-targeting chimera (LIVTAC) XZ1606, a novel proteolysis-targeting chimera (PROTAC) conjugated with a triantennary N-acetylgalactosamine (tri-GalNAc) moiety, to degrade BRD4 in hepatic stellate cells. In vitro, XZ1606 induced potent, dose- and time-dependent BRD4 degradation in LX-2 cells via the ubiquitin-proteasomal pathway after ASGPR-mediated endocytosis, with minimal cytotoxicity in normal hepatocytes. TGF-β-activated LX-2 cells exhibited significant reductions in fibrotic markers upon treatment, correlati

SUBMITTER: Yuan S 

PROVIDER: S-EPMC12315693 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature