Feng Ye, Kim Jong-Won, Xie Wen
Department of Endocrinology and Metabolic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Pharmacol Res. 2025 Jun;216:107779. doi: 10.1016/j.phrs.2025.107779. Epub 2025 May 14.
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are so-called xenobiotic nuclear receptors that play pivotal roles in xenobiotic metabolism and detoxification. Both receptors, highly expressed in the liver and intestine, also have endobiotic functions by regulating the homeostasis of endogenous chemicals. While their hepatic functions are well-documented, the functional roles of PXR and CAR in the gastrointestinal tract are less understood. This review highlights the intestinal functions of PXR and CAR, focusing on their involvement in colon cancer, host-microbiome interactions, inflammation, and gut barrier integrity. PXR exhibits dual roles in colon cancer, acting either as a tumor suppressor by inducing cell-cycle arrest or as a promoter of cancer aggressiveness through activating the FGF19 signaling. CAR, on the other hand, regulates intestinal barrier integrity and immune responses, particularly in the context of inflammatory bowel disease (IBD). Both PXR and CAR interact with gut microbiota, modulating microbial composition and the production of metabolites, such as indole-3-propionic acid (IPA) that influences the gut barrier function and inflammation. Activation of PXR also mitigates intestinal inflammation by antagonizing the NF-κB signaling, while CAR activation affects bile acid metabolism and T-cell homeostasis. These findings underscore the complex and context-dependent roles of PXR and CAR in the intestinal tracts, offering potential therapeutic targets for gastrointestinal diseases.
孕烷X受体（PXR）和组成型雄甾烷受体（CAR）是所谓的外源性核受体，在异生物代谢和解毒过程中发挥关键作用。这两种受体在肝脏和肠道中高度表达，通过调节内源性化学物质的稳态也具有内源性生物功能。虽然它们的肝脏功能已有充分记录，但PXR和CAR在胃肠道中的功能作用却知之甚少。本综述重点介绍了PXR和CAR的肠道功能，着重阐述它们在结肠癌、宿主-微生物群相互作用、炎症和肠道屏障完整性方面的作用。PXR在结肠癌中表现出双重作用，既可以通过诱导细胞周期停滞作为肿瘤抑制因子，也可以通过激活FGF19信号通路促进癌症侵袭性。另一方面，CAR调节肠道屏障完整性和免疫反应，特别是在炎症性肠病（IBD）的背景下。PXR和CAR都与肠道微生物群相互作用，调节微生物组成和代谢产物的产生，如影响肠道屏障功能和炎症的吲哚-3-丙酸（IPA）。PXR的激活还通过拮抗NF-κB信号通路减轻肠道炎症，而CAR的激活影响胆汁酸代谢和T细胞稳态。这些发现强调了PXR和CAR在肠道中复杂且依赖于背景的作用，为胃肠道疾病提供了潜在的治疗靶点。
