The tumor-suppressive role of Farnesoid X receptor (FXR) in colorectal tumorigenesis supports restoring FXR expression as a novel therapeutic strategy. However, the complicated signaling network and tumor heterogeneity hinder the effectiveness of FXR agonists in the clinical setting. These difficulties highlight the importance of identifying drug combinations with potency and specificity to enhance the antitumor effects of FXR agonists. In this study, we found that the β-catenin level affected the antitumor effects of the FXR agonist OCA on colon cancer cells. Mechanistic studies identified a novel FXR/β-catenin complex in colon cancer cells. Furthermore, the depletion of β-catenin expedited FXR nuclear localization and enhanced its occupancy of the SHP promoter and thereby sensitized colon cancer cells to OCA. Furthermore, we utilized a drug combination study and identified that the antiparasitic drug nitazoxanide (NTZ) abrogated β-catenin expression and acted synergistically with OCA in colon cancer cells. The combination of OCA plus NTZ exerts synergistic tumor inhibition in CRC both in vitro and in vivo by cooperatively upregulating SHP expression. In conclusion, our study offers useful evidence for the clinical use of FXR agonists combined with β-catenin inhibitors in combating CRC.

法尼醇 X 受体 (FXR) 在结直肠肿瘤发生中的肿瘤抑制作用支持恢复 FXR 表达作为一种新的治疗策略。然而，复杂的信号网络和肿瘤异质性阻碍了 FXR 激动剂在临床环境中的有效性。这些困难突出了识别具有效力和特异性的药物组合以增强 FXR 激动剂的抗肿瘤作用的重要性。在本研究中，我们发现 β-catenin 水平影响 FXR 激动剂 OCA 对结肠癌细胞的抗肿瘤作用。机理研究在结肠癌细胞中发现了一种新的 FXR/β-连环蛋白复合物。此外，β-连环蛋白的消耗加速了 FXR 核定位并增强了其对 SHP 启动子的占据，从而使结肠癌细胞对 OCA 敏感。此外，我们利用药物组合研究并确定抗寄生虫药物硝唑尼特 (NTZ) 消除了 β-连环蛋白的表达并与结肠癌细胞中的 OCA 协同作用。OCA 和 NTZ 的组合通过协同上调 SHP 的表达，在体外和体内对 CRC 产生协同的肿瘤抑制作用。总之，我们的研究为 FXR 激动剂联合 β-连环蛋白抑制剂在对抗 CRC 中的临床应用提供了有用的证据。