Pregnane X Receptor (PXR/NR1I2): Linking Drug Metabolism, Bile Acid Detoxification, and Cholesterol Homeostasis

Pregnane X receptor (PXR; NR1I2) is a promiscuous ligand-activated nuclear receptor traditionally recognized as a master regulator of xenobiotic detoxification. Beyond xenobiotic detoxification, emerging evidence implicates PXR as a pivotal regulator of both cholesterol and bile acid metabolism, integrating sterol balance with detoxification pathways. While bile acid regulation by PXR is well established, its contribution to dyslipidemia and cardiovascular risk remains an emerging area of translational relevance Mechanistically, PXR activation induces CYP3A4 and other phase I/II enzymes, elevating plasma 4β-hydroxycholesterol as a biomarker of receptor activity. Crosstalk with sterol regulatory networks, particularly SREBP2, drives upregulation of HMGCR and PCSK9, enhancing cholesterol synthesis and LDL-C levels. Interactions with LXR and FXR further integrate PXR into sterol and bile-acid signaling loops. Pharmacologic activation by diverse agents-including rifampicin, azoles, antiretrovirals, and herbal products-can disrupt lipid balance, while NR1I2 polymorphisms shape interindividual susceptibility. This review synthesizes mechanistic, pharmacogenomic, and regulatory insights to highlight PXR as both a metabolic liability in polypharmacy and a potential therapeutic target in dyslipidemia and liver disease.This review highlights PXR's dual role at the intersection of bile acid detoxification and cholesterol regulation, clarifying mechanistic, pharmacogenomic, and clinical implications.