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NRF2 Stabilization by Isoform-Specific Nuclear Phosphoinositides in Stress Response
Yiting Tang1,2, Yu Chen1,2, Noah D Carrillo3,4
1Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine and SUSTech Homeostatic Medicine Institute (SHMI), Southern University of Science and Technology, Shenzhen 518055, China.
Oral Science and Homeostatic Medicine
|March 30, 2026
Summary
Oxidative stress stabilizes nuclear factor erythroid 2-related factor 2 (NRF2) via a novel pathway involving PIPKIγ and PtdIns(4,5)P2. This mechanism protects NRF2 from degradation, offering new cancer therapeutic targets.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Phosphoinositide signaling was traditionally viewed as membrane-bound.
- Emerging research indicates a nuclear lipid signaling pathway influencing protein stability.
Purpose of the Study:
- To elucidate a novel mechanism for nuclear factor erythroid 2-related factor 2 (NRF2) stabilization.
- To investigate the role of nuclear phosphoinositides in regulating protein stability.
Main Methods:
- Investigated the interaction between type I phosphatidylinositol 4-phosphate 5-kinase γ (PIPKIγ), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), and small heat shock protein 27 (HSP27) in NRF2 stabilization.
- Examined the NRF2 stabilization pathway independent of the KEAP1 mechanism.
- Compared the NRF2 pathway with the previously described p53 stabilization pathway involving PIPKIα.
Main Results:
- Discovered that oxidative stress induces NRF2 stabilization through a nuclear complex of PIPKIγ, PtdIns(4,5)P2, and HSP27.
- Demonstrated that PIPKIγ generates nuclear PtdIns(4,5)P2, which recruits HSP27 to stabilize NRF2 against proteasomal degradation.
- Showed this stabilization occurs independently of the canonical KEAP1 pathway.
Conclusions:
- Nuclear phosphoinositide signaling provides a mechanism for stress-induced protein stabilization.
- Isoform-specific PIP kinases (PIPKIγ for NRF2, PIPKIα for p53) highlight a principle in nuclear signaling.
- This pathway reveals potential therapeutic vulnerabilities in cancer treatment.
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