Abstract

The Pregnan X Receptor (PXR, NR1I2) is a critical nuclear receptor primarily recognized for its role as a master xenobiotic sensor, regulating the expression of numerous genes involved in drug metabolism and transport. However, its functional status under conditions of cellular stress, particularly oxidative stress, remains a significant area of investigation in membrane and cell biology. This study was designed to evaluate the effect of elevated reactive oxygen species (ROS) on the functioning of PXR, including its expression, subcellular localization, and transcriptional activity toward target genes such as CYP3A4 and MDR1. Using *in vitro* cell culture models, we demonstrate that oxidative stress significantly modulates PXR function, leading to a reduction in its ligand-dependent transcriptional activity and altered nuclear-cytoplasmic shuttling. Mechanistically, this effect is linked to specific post-translational modifications of the receptor induced by ROS. Crucially, we found that PXR activation, in turn, confers a protective effect against oxidative damage by upregulating key antioxidant defense genes. These findings reveal a novel, reciprocal regulatory loop between PXR and the cellular redox state, highlighting PXR's role not only in xenobiotic clearance but also in maintaining cellular homeostasis and membrane integrity under pathological conditions. This has important implications for understanding drug efficacy and toxicity in diseases associated with high oxidative burden.