PXR activation ameliorates hyperuricemic nephropathy via NRF2 signaling

Long-term hyperuricemia (HUA) constitutes a major determinant of HUA-induced nephropathy (HN), yet current uricosuric drugs often exhibit limited efficacy and may pose a risk of kidney damage. Pregnane X receptor (PXR) plays a key role in xenobiotic and endobiotic metabolism homeostasis and has demonstrated anti-inflammatory, anti-fibrotic, and renoprotective properties. However, the role of PXR in regulating uric acid homeostasis and mitigating HN remains unclear. This study reveals PXR activation modulates uric acid homeostasis through dual suppression of xanthine oxidase (XOD) activity and enhanced ATP-binding cassette sub-family G member 2 (ABCG2) expression, thereby reducing uric acid accumulation and ameliorating renal injury. Mechanistically, PXR could interact with nuclear factor erythroid 2-related factor 2 (NRF2) to facilitate its nuclear translocation. Furthermore, we found that PXR activation inhibited K48-linked ubiquitination of NRF2 and promoted phosphorylation of NRF2 at S40, thereby activating NRF2 signaling and upregulating downstream target genes. This study elucidates PXR's dual role in regulating uric acid metabolism and attenuating HN, providing potential novel therapeutic targets for HN management. • Excessive uric acid suppresses the expression and activation of PXR. • PCN-induced activation of mPXR modulates uric acid homeostasis and attenuates renal injury in HN mice. • Pxr knockout exacerbates uric acid imbalance and renal injury in HN mice. • The protective effect of PXR activation on uric acid homeostasis and high uric acid-induced kidney injury is mediated through NRF2. • PXR interacts with NRF2 and promotes its phosphorylation at S40 to activate NRF2 signaling.