Pregnane X receptor in disease: From xenobiotic sensor to therapeutic target

The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor that serves as a classical and central regulator of xenobiotic metabolism and endogenous metabolic homeostasis. Recent studies have revealed that PXR plays critical roles in the pathogenesis and progression of diseases across multiple organ systems, including hepatic, gastrointestinal, renal, cardiovascular, central nervous system, and reproductive-endocrine disorders. Notably, PXR activation can exert protective effects by improving metabolic balance, reducing inflammation, and preventing fibrosis; however, it may promote disease progression in certain settings, highlighting its dual roles. Advances in pharmacological research have led to the identification of numerous PXR agonists and antagonists, including endogenous ligands, natural products, and synthetic compounds, many of which show therapeutic potential. This review summarizes recent progress on the pharmacological roles of PXR in organ-specific diseases and provides an overview of current strategies targeting PXR, offering new insights into its potential as a therapeutic target. SIGNIFICANCE STATEMENT: The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor traditionally recognized as a master regulator of xenobiotic metabolism. Growing evidence demonstrates that PXR plays important roles beyond drug metabolism, regulating the pathogenesis and progression of hepatic, gastrointestinal, renal, cardiovascular, central nervous system, and reproductive-endocrine diseases. This review summarizes current knowledge on PXR's organ-specific functions and pharmacological modulation, highlighting PXR as a promising drug target across multiple disease contexts.