研究表明，重楼素 I (PPI) 对肝细胞癌 (HCC) 具有有效的抗肿瘤活性。然而，这种作用的精确分子机制和直接靶点仍不清楚。本研究的目的是发现PPI治疗HCC的分子靶点和确切机制。采用多种HCC细胞和斑马鱼异种移植模型来检验PPI抗HCC的疗效。通过蛋白质组微阵列、表面等离子共振 (SPR) 分析、小分子转染和分子对接来确认 PPI 的直接结合靶点。然后使用转录组和蛋白质印迹来确定确切的反应机制。最后，通过小鼠肿瘤异种移植研究验证了PPI的抗癌作用及其确切机制以及安全性。结果表明，在两种细胞和斑马鱼模型的体外研究中，PPI均具有显着的抗HCC活性。 。值得注意的是，PPI 通过直接结合锌指和含 BTB 结构域的 16 (ZBTB16) 蛋白而选择性增强其作用。此外，ZBTB16 的特异性敲低显着减弱了该基因过度表达引起的 PPI 依赖性 HCC 细胞增殖和迁移抑制。转录组和Western blotting也证实ZBTB16和PPI之间的相互作用也激活了PPARγ/RXRα通路。最后，小鼠实验证实了 PPI 治疗 HCC 的有效性和安全性。我们的结果表明，ZBTB16 是 HCC 有前途的药物靶点，PPI 作为有效的 ZBTB16 激动剂，有潜力通过调节 ZBTB16/PPARγ 作为 HCC 治疗剂/RXRα 信号轴。© 2024。作者。

Studies have reported that polyphyllin I (PPI) had effective anti-tumor activity against hepatocellular carcinoma (HCC). However, the precise molecular mechanism of this action and the direct target remain unclear. The aim of this study was to discover the molecular targets and the exact mechanism of PPI in the treatment of HCC.Various HCC cells and Zebrafish xenotransplantation models were used to examine the efficacy of PPI against HCC. A proteome microarray, surface plasmon resonance (SPR) analysis, small molecule transfection, and molecular docking were conducted to confirm the direct binding targets of PPI. Transcriptome and Western blotting were then used to determine the exact responding mechanism. Finally, the anticancer effect and its precise mechanism, as well as the safety of PPI, were verified using a mouse tumor xenograft study.The results demonstrated that PPI had significant anticancer activity against HCC in both in vitro studies of two cells and the zebrafish model. Notably, PPI selectively enhanced the action of the Zinc finger and BTB domain-containing 16 (ZBTB16) protein by directly binding to it. Furthermore, specific knockdown of ZBTB16 markedly attenuated PPI-dependent inhibition of HCC cell proliferation and migration caused by overexpression of the gene. The transcriptome and Western blotting also confirmed that the interaction between ZBTB16 and PPI also activated the PPARγ/RXRα pathway. Finally, the mouse experiments confirmed the efficacy and safety of PPI to treat HCC.Our results indicate that ZBTB16 is a promising drug target for HCC and that PPI as a potent ZBTB16 agonist has potential as a therapeutic agent against HCC by regulating the ZBTB16/PPARγ/RXRα signaling axis.© 2024. The Author(s).