Liver-targeted degradation of BRD4 reverses hepatic fibrosis and enhances metabolism in murine models
文献类型：期刊论文
| 作者 | Yuan, Shengjie7; Nisar, Ayesha7; Chen, Chuanjie6; Dong, Xin7; Pan, Yongzhang7; Zi, Meiting7; Wang, Qiong5; Khan, Sawar3,4; Guo, Yaxun2; Zhang, Xuan1,6 |
| 刊名 | THERANOSTICS
 |
| 出版日期 | 2025 |
| 卷号 | 15期号:15页码:7270-7290 |
| 关键词 | asialoglycoprotein receptor BRD4 degradation liver fibrosis liver-targeting chimera proteolysis-targeting chimera |
| ISSN号 | 1838-7640 |
| DOI | 10.7150/thno.113852 |
| 通讯作者 | Zhang, Xuan(zhangxuan@simm.ac.cn) ; He, Yonghan(heyonghan@mail.kiz.ac) |
| 英文摘要 | 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-beta-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. |
| WOS关键词 | EXTRACELLULAR-MATRIX ; MECHANISMS ; DISEASE ; CHIMERAS |
| 资助项目 | Yunnan Fundamental Research Projects[202201AS070038] ; Yunnan Fundamental Research Projects[202305AH340006] ; National Key R&D Program of China[2023YFC3603300] ; National Natural Science Foundation of China[82171558] ; National Natural Science Foundation of China[82471599] ; National Natural Science Foundation of China[22277131] ; CAS Light of West China Program[xbzg-zdsys-202312] ; Yunnan Revitalization Talent Support Program Young Talent Project ; Pioneer Hundred Talents Program of the Chinese Academy of Sciences |
| WOS研究方向 | Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:001532197900003 |
| 出版者 | IVYSPRING INT PUBL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321102]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhang, Xuan; He, Yonghan |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Shandong Univ, Dept Breast Surg, Hosp 2, Jinan, Shandong, Peoples R China 3.Univ Lahore, Inst Mol Biol & Biotechnol, Lahore, Pakistan 4.Cent South Univ, Sch Life Sci, Dept Cell Biol, Changsha, Hunan, Peoples R China 5.Chinese Acad Sci, Natl Resource Ctr Nonhuman Primates, Kunming Inst Zool, Kunming, Yunnan, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai 201203, Peoples R China 7.Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Evolut & Anim Models, Key Lab Hlth Aging Res Yunnan Prov, Kunming, Yunnan, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yuan, Shengjie,Nisar, Ayesha,Chen, Chuanjie,et al. Liver-targeted degradation of BRD4 reverses hepatic fibrosis and enhances metabolism in murine models[J]. THERANOSTICS,2025,15(15):7270-7290. |
| APA | Yuan, Shengjie.,Nisar, Ayesha.,Chen, Chuanjie.,Dong, Xin.,Pan, Yongzhang.,...&He, Yonghan.(2025).Liver-targeted degradation of BRD4 reverses hepatic fibrosis and enhances metabolism in murine models.THERANOSTICS,15(15),7270-7290. |
| MLA | Yuan, Shengjie,et al."Liver-targeted degradation of BRD4 reverses hepatic fibrosis and enhances metabolism in murine models".THERANOSTICS 15.15(2025):7270-7290. |
入库方式： OAI收割
来源：上海药物研究所
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