@article{Tang2026, 
author = {Yiting Tang and Yu Chen and Noah D. Carrillo and Vincent L. Cryns and Richard A. Anderson and Jichao Sun and Mo Chen},
title = {NRF2 stabilization by isoform-specific nuclear phosphoinositides in stress response},
year = {2026},
journal = {Oral Science and Homeostatic Medicine},
volume = {2},
number = {1},
pages = {9610041},
keywords = {nucleus, NRF2, PIP signaling, PIPKIγ, PtdIns(4,5)P2},
url = {https://www.sciopen.com/article/10.26599/OSHM.2026.9610041},
doi = {10.26599/OSHM.2026.9610041},
abstract = {Phosphoinositide signaling has long been regarded as a membrane-confined regulatory system; however, emerging evidence reveals a distinct nuclear lipid signaling axis that directly regulates protein stability. A recent study details a previously unrecognized mechanism controlling nuclear factor erythroid 2-related factor 2 (NRF2), demonstrating that oxidative stress induces its stabilization through a nuclear complex composed of 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 this pathway, PIPKIγ generates a stably associated nuclear pool of PtdIns(4,5)P2 on NRF2, promoting HSP27 recruitment and protecting NRF2 from proteasomal degradation, independent of the canonical Kelch-like ECH-associated protein 1 (KEAP1) mechanism. This pathway parallels a nuclear phosphoinositide-dependent stabilization paradigm previously described for tumor protein p53 (p53), in which another 5-kinase, type I phosphatidylinositol 4-phosphate 5-kinase α (PIPKIα), mediates p53 stabilization. The isoform-specific engagement of PIP kinases highlights a fundamental principle of nuclear signaling that enables stress-selective transcriptional regulation, exposing new therapeutic vulnerabilities in cancer.}
}