Rubidium chloride induces ferroptosis in glioblastoma cells by disrupting glutathione metabolism and redox homeostasis

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor in adults, characterized by poor prognosis and resistance to conventional therapies. Ferroptosis, a regulated form of iron-dependent cell death marked by lipid peroxidation and redox imbalance, has emerged as a promising therapeutic target in GBM. Rubidium ions (Rb⁺), chemically similar to potassium, have shown cytotoxic effects in tumor cells; however, their role in ferroptosis remains unknown. U87 and U251 GBM cell lines were treated with RbCl at varying concentrations. Reactive oxygen species (ROS), intracellular ferrous iron (Fe²⁺), glutathione (GSH) levels, and lipid peroxidation were assessed. Transmission electron microscopy (TEM) was used to assess mitochondrial ultrastructure. Untargeted metabolomics profiling was conducted using liquid chromatography–tandem mass spectrometry (LC-MS/MS), followed by KEGG pathway enrichment analysis. Ferroptosis-specific inhibitors (Fer-1 and Lip-1) were applied to validate the mode of cell death. RbCl treatment significantly increased ROS levels, Fe²⁺ accumulation, and malondialdehyde (MDA), while depleting GSH in a dose-dependent manner. TEM analysis revealed ferroptosis-characteristic mitochondrial shrinkage and membrane disruption. Metabolomics profiling showed significant alterations in glutamate and GSH metabolism pathways. Ferroptosis inhibitors partially reversed these changes, confirming the ferroptotic nature of Rb⁺-induced cell death. Rb⁺ induces ferroptosis in GBM cells by disrupting redox homeostasis and impairing glutathione metabolism. These findings uncover a novel function of rubidium as a ferroptosis modulator and support its potential as a redox-targeting therapeutic strategy in glioblastoma.