活性氧（ROS）是由有氧代谢产生的，它们的有害影响可以通过细胞抗氧化反应来缓冲，从而防止氧化应激。核因子红细胞 2 相关因子 2 (NRF2) 是抗氧化反应的主要转录调节因子。 E3 连接酶（包括 Kelch 样 ECH 相关蛋白 1 (KEAP1)）对 NRF2 进行泛素依赖性降解，从而使 NRF2 的基础水平保持在较低水平。在这里，我们表明NRF2的稳定性和功能受到I型磷脂酰肌醇磷酸激酶g（PIPKIg）的调节，PIPKIg与NRF2结合并将其产物磷脂酰肌醇4,5-二磷酸（PtdIns(4,5)P 2 ）转移至NRF2 。 PtdIns(4,5)P 2 结合将小热休克蛋白 HSP27 招募到复合物中。沉默 PIPKIg 或 HSP27 会破坏 NRF2 的稳定性，降低其靶基因 HO-1 的表达，并使细胞对氧化应激敏感。这些数据证明了磷酸肌醇和HSP27在调节NRF2方面具有意想不到的作用，并指出PIPKIg和HSP27作为在癌症中破坏NRF2稳定的药物靶标。磷酸肌醇通过PIPKIγ与NRF2偶联，并且HSP27被招募并稳定NRF2，从而促进应激抵抗。

Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase g (PIPKIg), which binds NRF2 and transfers its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) to NRF2. PtdIns(4,5)P 2 binding recruits the small heat shock protein HSP27 to the complex. Silencing PIPKIg or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected role of phosphoinositides and HSP27 in regulating NRF2 and point to PIPKIg and HSP27 as drug targets to destabilize NRF2 in cancer.Phosphoinositides are coupled to NRF2 by PIPKIγ, and HSP27 is recruited and stabilizes NRF2, promoting stress-resistance.