Liver-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, correlating with decreased BRD4 levels. <i>In vivo</i>, XZ1606 (1.5 mg/kg) significantly ameliorated fibrosis in both CCl₄-induced and choline-deficient L-amino acid-defined high-fat diet (CDAA-HFD) mouse models, as evidenced by reduced collagen deposition and normalized transcriptomic and metabolomic profiles. Notably, key proinflammatory and profibrotic genes and metabolites, including 1-Methylnicotinamide, were downregulated. <b>Conclusion:</b> These results highlight the therapeutic potential of LIVTAC XZ1606 in reversing liver fibrosis and steatosis through targeted BRD4 degradation, offering a novel and selective approach for chronic liver disease treatment.