Yuan Shengjie, Nisar Ayesha, Chen Chuanjie, Dong Xin, Pan Yongzhang, Zi Meiting, Wang Qiong, Khan Sawar, Guo Yaxun, Zhang Xuan, He Yonghan
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.
Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Theranostics. 2025 Jun 18;15(15):7270-7290. doi: 10.7150/thno.113852. eCollection 2025.
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. We repurposed the liver-targeting chimera (LIVTAC) XZ1606, a novel proteolysis-targeting chimera (PROTAC) conjugated with a triantennary -acetylgalactosamine (tri-GalNAc) moiety, to degrade BRD4 in hepatic stellate cells. , 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. , 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. 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.
肝纤维化的特征是细胞外基质过度沉积，是肝硬化和肝细胞癌的先兆，目前的治疗方法常常受到脱靶毒性的限制。我们将肝脏靶向嵌合体（LIVTAC）XZ1606进行了重新利用，它是一种新型的蛋白水解靶向嵌合体（PROTAC），与三分支N-乙酰半乳糖胺（tri-GalNAc）部分结合，用于在肝星状细胞中降解BRD4。XZ1606在通过ASGPR介导的内吞作用后，通过泛素-蛋白酶体途径在LX-2细胞中诱导了强效的、剂量和时间依赖性的BRD4降解，对正常肝细胞的细胞毒性最小。经TGF-β激活的LX-2细胞在治疗后纤维化标志物显著减少，这与BRD4水平降低相关。XZ1606（1.5mg/kg）在四氯化碳诱导和胆碱缺乏的L-氨基酸限定高脂饮食（CDAA-HFD）小鼠模型中均显著改善了纤维化，这通过胶原沉积减少以及转录组和代谢组谱正常化得到证明。值得注意的是，包括1-甲基烟酰胺在内的关键促炎和促纤维化基因及代谢物均下调。这些结果突出了LIVTAC XZ1606通过靶向降解BRD4来逆转肝纤维化和脂肪变性的治疗潜力，为慢性肝病治疗提供了一种新的选择性方法。
