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Cytoplasmic PXR regulates glucose metabolism by binding mRNAs and modulating their stability
Xiaofei Wang1, Zehua Wang1, Sihan Li1
1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
Nature Structural & Molecular Biology
|August 12, 2025
Summary
Pregnane X receptor (PXR) acts as an RNA-binding protein, stabilizing specific mRNAs in the cytoplasm. This newly discovered function impacts metabolic reprogramming and promotes cancer cell proliferation.
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- Pregnane X receptor (PXR) is a nuclear receptor known as a master regulator of xenobiotic metabolism.
- PXR's established role involves transcriptional regulation within the nucleus.
Purpose of the Study:
- To investigate a potential non-transcriptional role of PXR in gene regulation.
- To characterize PXR's interaction with mRNA and its functional consequences in cellular processes.
Main Methods:
- Enhanced ultraviolet crosslinking and immunoprecipitation (eCLIP) to identify PXR-bound mRNAs.
- Analysis of PXR-bound transcripts in various cancer cell lines and normal liver tissues.
- Investigating the interaction of cytoplasmic PXR with RNA-binding proteins and its effect on mRNA stability.
Main Results:
- PXR binds to mRNAs, including those involved in metabolic reprogramming and lipid metabolism.
- Cytoplasmic PXR binds and stabilizes mature mRNAs with C+G-rich sequences via its zinc-finger domain.
- PXR interacts with RNase inhibitor RNH1 to regulate RNA stability.
- In colorectal cancer, cytoplasmic PXR stabilizes SLC2A1 mRNA, enhancing glucose uptake, proliferation, and cancer development.
Conclusions:
- PXR functions as an RNA-binding protein in the cytoplasm, independent of its nuclear transcriptional role.
- Cytoplasmic PXR regulates mRNA stability, influencing cellular metabolism and cancer progression.
- This study reveals a novel dimension of PXR-mediated gene regulation impacting RNA biology.
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