Pregnane X receptor as a therapeutic target for cholestatic liver injury

Abstract

Cholestatic liver injury (CLI) is caused by toxic bile acids (BAs) accumulation in the liver and can lead to inflammation and liver fibrosis. The mechanisms underlying CLI development remain unclear, and this disease has no effective cure. However, regulating BA synthesis and homeostasis represents a promising therapeutic strategy for CLI treatment. Pregnane X receptor (PXR) plays an essential role in the metabolism of endobiotics and xenobiotics via the transcription of metabolic enzymes and transporters, which can ultimately modulate BA homeostasis and exert anticholestatic effects. Furthermore, recent studies have demonstrated that PXR exhibits antifibrotic and anti-inflammatory properties, providing novel insights into treating CLI. Meanwhile, several drugs have been identified as PXR agonists that improve CLI. Nevertheless, the precise role of PXR in CLI still needs to be fully understood. This review summarizes how PXR improves CLI by ameliorating cholestasis, inhibiting inflammation, and reducing fibrosis and discusses the progress of promising PXR agonists for treating CLI.

Keywords:

• Pregnane X receptor
• cholestasis
• inflammation
• fibrosis
• agonists

Author contributions

Conceptualization, H.L.; supervision, H.L. and Y.Z.; writing—original draft, HL; writing—review and editing, H.L., B.X.W., and M.Q.F. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81930114), Key-Area Research and Development Program of Guangdong Province (Grant No. 2020B1111100004), and the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Laboratory, Grant No. 2020B1212030006). We would like to thank Dr. Joseph Elliot at the University of Kansas for her assistance with the manuscript’s English language and grammatical editing.