biostudies-literatureUnknown15(15)Yuan S<b>Background:</b> 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. <b>Methods and results:</b> We repurposed the liver-targeting chimera (LIVTAC) XZ1606, a novel proteolysis-targeting chimera (PROTAC) conjugated with a triantennary <i>N</i>-acetylgalactosamine (tri-GalNAc) moiety, to degrade BRD4 in hepatic stellate cells. <i>In vitro</i>, 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, correlatiTheranostics7270-7290https://www.ebi.ac.uk/biostudies/studies/S-EPMC12315693biostudies-literatureLiver-targeted degradation of BRD4 reverses hepatic fibrosis and enhances metabolism in murine models.PMC12315693Yuan SPan YWang QHe YDong XGuo YZi MZhang XChen CNisar AKhan SfalseLiver-targeted degradation of BRD4 reverses hepatic fibrosis and enhances metabolism in murine models.<b>Background:</b> 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. <b>Methods and results:</b> We repurposed the liver-targeting chimera (LIVTAC) XZ1606, a novel proteolysis-targeting chimera (PROTAC) conjugated with a triantennary <i>N</i>-acetylgalactosamine (tri-GalNAc) moiety, to degrade BRD4 in hepatic stellate cells. <i>In vitro</i>, 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, correlati2025-01-01T00:00:00Z20252025-08-27T03:07:03.125Z2025-08-27T03:07:03.125ZS-EPMC123156934075637010.7150/thno.113852