Niu Dou, Wu Xiaolei, Zhang Yuxin, Wang Xueliang, Shiu-Hin Chan Daniel, Jing Shaozhen, Wong Chun-Yuen, Wang Wanhe, Leung Chung-Hang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi 710072, China.
J Adv Res. 2025 May;71:307-316. doi: 10.1016/j.jare.2024.10.028. Epub 2024 Oct 28.
The farnesoid X receptor (FXR) is a crucial regulator in the intestine, maintaining bile acid homeostasis. Inhibiting intestinal FXR shows promise in managing inflammatory bowel and liver diseases by reducing bile acid accumulation. Additionally, changes in FXR expression could serve as a potential biomarker for intestinal diseases. Therefore, developing an imaging probe for FXR holds significant potential for the early detection, simultaneous treatment, and monitoring of FXR-related diseases.
The study aimed to develop a bioimaging probe for FXR by conjugating obeticholic acid (OCA), an FXR agonist, to an iridium(III) complex, and to investigate its application for targeting FXR in intestinal cells.
OCA was conjugated to an iridium(III) complex to generate the novel complex 1. The effect of complex 1 on FXR activity, nuclear translocation, and downstream targets was investigated in intestinal epithelial cells using various biochemical and cellular assays. Additionally, the photophysical properties of complex 1 were assessed for FXR imaging.
Complex 1 retained the desirable photophysical properties for monitoring FXR in intestinal cells while reversing OCA's activity from agonistic to antagonistic. It disrupted FXR-RXR heterodimerization, inhibited FXR nuclear translocation, and downregulated downstream targets responsible for bile acid absorption, transport, and metabolism in intestinal epithelial cells.
The study successfully developed an imaging probe and modulator of FXR by conjugating OCA to an iridium(III) complex. Complex 1 retained the favorable photophysical properties of the iridium(III) complex, while reversing OCA's activity from agonistic to antagonistic. The findings highlight the exciting application of using metals to tailor the activity of nuclear receptor modulators in living systems.
法尼醇X受体（FXR）是肠道中的关键调节因子，维持胆汁酸稳态。抑制肠道FXR通过减少胆汁酸积累，在治疗炎症性肠病和肝病方面显示出前景。此外，FXR表达的变化可作为肠道疾病的潜在生物标志物。因此，开发一种用于FXR的成像探针对于FXR相关疾病的早期检测、同步治疗和监测具有重大潜力。
本研究旨在通过将FXR激动剂奥贝胆酸（OCA）与铱（III）配合物偶联，开发一种用于FXR的生物成像探针，并研究其在肠道细胞中靶向FXR的应用。
将OCA与铱（III）配合物偶联，生成新型配合物1。使用各种生化和细胞分析方法，研究配合物1对肠道上皮细胞中FXR活性、核转位和下游靶点的影响。此外，评估配合物1的光物理性质以用于FXR成像。
配合物1保留了用于监测肠道细胞中FXR的理想光物理性质，同时将OCA的活性从激动剂转变为拮抗剂。它破坏了FXR-RXR异二聚体化，抑制了FXR核转位，并下调了负责肠道上皮细胞中胆汁酸吸收、转运和代谢的下游靶点。
本研究通过将OCA与铱（III）配合物偶联，成功开发了一种FXR的成像探针和调节剂。配合物1保留了铱（III）配合物良好的光物理性质，同时将OCA的活性从激动剂转变为拮抗剂。这些发现突出了利用金属来定制活体内核受体调节剂活性的令人兴奋的应用。
