Inherent electrochemical activity of extrachromosomal DNA hub shapes spatial redox environment in nucleus

Extrachromosomal DNA (ecDNA) is a key element driving the malignant progression of tumors. Since ecDNA lacks canonical high-order chromatin compaction, how it maintains structural and functional stability in highly oxidizing tumor environments remains unclear. Using metabolomics, biochemistry, and imaging assays in human cancer cells and mouse models, we herein show that ecDNA hub establishes an active electrochemical environment, which drives the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) through a non-enzymatic mechanism. GSH forms a protective "cloud" around ecDNA hubs, shielding ecDNA from damage and sustaining oncogene expression. Lastly, using spermidine, which disrupts the interfacial environment of ecDNA hubs, we found that affecting the redox balance of ecDNA hubs drives tumor death. This study uncovers a non-enzymatic function of ecDNA hubs that establishes a self-reinforcing maintenance loop to regulate spatial redox environments, revealing an electrochemical environment-dependent redox-regulation strategy in cancer biology.