{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Guo M"],"funding":["Key Laboratory of Diagnosis and Treatment of Severe Hepato-pancreatic Diseases of Zhejiang Province","National Natural Science Foundation of China"],"pagination":["e04372"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12376573"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["12(30)"],"pubmed_abstract":["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."],"journal":["Advanced science (Weinheim, Baden-Wurttemberg, Germany)"],"pubmed_title":["PIP5K1A Suppresses Ferroptosis and Induces Sorafenib Resistance by Stabilizing NRF2 in Hepatocellular Carcinoma."],"pmcid":["PMC12376573"],"funding_grant_id":["G2023005","82373086","82102761"],"pubmed_authors":["Fang Y","Guo M","Zhou L","Li J","Xia J","Qi Z","Xu R","Chen S","Liu T","Sun J"],"additional_accession":[]},"is_claimable":false,"name":"PIP5K1A Suppresses Ferroptosis and Induces Sorafenib Resistance by Stabilizing NRF2 in Hepatocellular Carcinoma.","description":"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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Aug","modification":"2026-05-09T19:11:05.091Z","creation":"2026-04-08T01:09:34.756Z"},"accession":"S-EPMC12376573","cross_references":{"pubmed":["40405713"],"doi":["10.1002/advs.202504372"]}}