PIP5K1A Suppresses Ferroptosis and Induces Sorafenib Resistance by Stabilizing NRF2 in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, has emerged as a promising strategy for cancer treatment. However, the development of ferroptosis resistance limits the efficacy of such treatments. This study reports that phosphatidylinositol 4-phosphate 5-kinase 1 alpha (PIP5K1A) promotes HCC tumorigenesis and predicts poor prognosis in HCC patients. Knockdown of PIP5K1A enhances lipid peroxidation and increases sensitivity to sorafenib-induced ferroptosis by inhibiting the activation of downstream ferroptosis-related genes regulated by nuclear factor erythroid-2-related factor 2 (NRF2). Mechanistically, PIP5K1A competitively binds to the Kelch domain of Kelch-like ECH-associated protein 1 in a kinase-independent manner, leading to NRF2 escaping from ubiquitination degradation, thereby promoting NRF2-dependent transcription and suppressing ferroptosis. Furthermore, ISA-2011B, a PIP5K1A-specific inhibitor, effectively inhibits HCC growth and sensitized HCC cells to sorafenib. In conclusion, PIP5K1A is a promising therapeutic target for improving the efficacy of sorafenib and other ferroptosis inducers in HCC.