Work

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

Year: 2025

Type: article

Abstract: BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Source: Cancer Cell International

DOI: 10.1186/s12935-025-04085-2

Authors: Zairan Wang, Zijun Zhao, Jingzhi Fan, Jun Gao, Yongning Li