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

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

  • Theranostics. 2025 Jun 18;15(15):7270-7290. doi: 10.7150/thno.113852.
Shengjie Yuan 1,  Ayesha Nisar 1,  Chuanjie Chen 2,  Xin Dong 1,  Yongzhang Pan 1,  Meiting Zi 1,  Qiong Wang 3,  Sawar Khan 4 5,  Yaxun Guo 6,  Xuan Zhang 2 7,  Yonghan He 1 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
  • 2 Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 3 National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
  • 4 Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, China.
  • 5 Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan.
  • 6 Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China.
  • 7 University of Chinese Academy of Sciences, Beijing, China.
PMID: 40756370 DOI: 10.7150/thno.113852
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, correlating with decreased BRD4 levels. In vivo, 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. Conclusion: 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.

Keywords

BRD4 degradation; asialoglycoprotein receptor; liver fibrosis; liver-targeting chimera; proteolysis-targeting chimera.

Figures
Products