Pregnane X receptor (PXR) as a prognostic marker and therapeutic target in kidney renal clear cell carcinoma (KIRC) via AMPK pathway regulation.

Kidney renal clear cell carcinoma (KIRC) is the most common histological subtype of renal cell carcinoma (RCC), characterized by high metastatic potential and mortality, accounting for over 75% of RCC patients worldwide. However, KIRC patients often exhibit poor prognosis due to the absence of effective and sensitive biomarkers for early detection. As a key xenobiotic and endobiotic receptor in humans, the pregnane X receptor (PXR, NR1I2) exerts regulatory functions on various biological signaling pathways—most of which are associated with tumorigenesis. In this study, we aimed to elucidate the role of PXR in KIRC and investigate its underlying mechanisms. Using The Cancer Genome Atlas (TCGA) database and our clinical KIRC samples, we analyzed the expression profile and prognostic value of PXR. Results showed that PXR was significantly upregulated in KIRC tumor tissues, and high PXR levels were associated with poor overall survival in KIRC patients. Further in vitro experiments demonstrated that modulating PXR markedly influenced KIRC cell proliferation, invasion, migration, and metastasis. RNA sequencing revealed that PXR knockdown in KIRC cells perturbed multiple cell signaling pathways. Mechanistic investigations showed that PXR down-regulation promoted the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and affected the proliferation, apoptosis and invasion of KIRC cells. Our findings indicate that PXR is consistently upregulated in KIRC tissues and correlates with poor patient prognosis, suggesting it could serve as a potential biomarker for the diagnosis and prognosis of KIRC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-19812-y.