Ferroptosis is determined by chloride ions

• DOI: 10.1101/2023.02.07.526847
• Publication Date: 2023-02-08T15:35:12Z
• Authors: Dichun Huang; Zhangshuai Dai; Chao Wang; Haiying Mai; Junyi Zhao; Lingbo Cao; Sijie Wang; Zhun Dai; Kun Xu; Ronghan He; Shaoshen Zhu; Yanchen Chen; Tiejun Bing; Xinzhou Zhu; Ting Gang Chew; Junqi Huang

AbstractFerroptosis has emerged as a deliberate type of programmed cell death that manifests marked importance ubiquitously in health and diseases. However, after a decade of research, the mechanisms of ferroptosis execution remain unclear. Here we identify chloride ions (Cl-) as essential determinants of ferroptosis. Water homeostasis manipulated by extracellular solute concentration disrupts ferroptotic cell death. Hyperosmotic stress attenuates ferroptosis and endues cells with high lipid peroxidation. Analyses of a fluorescent chloride probe show that Cl-fluxes into the cytoplasm during ferroptosis, substantiating a role for Cl-to drive water flow. Depletion of extracellular chloride ions ([Cl-]o) from culture media congruously confers resistance to ferroptosis. The [Cl-]o-depleted ferroptotic cells fall into two populations: cells with low lipid peroxidation; cells with high lipid peroxidation but not cell swelling or cell rupture. Contrarily, solitary [Cl-]ooverload is sufficient to elicit ferroptosis without canonical ferroptosis inducers. Further experiments show that ferroptotic cells depolarize and [Cl-]ois positively correlated with this process. Membrane depolarization upregulates the level of lipid peroxidation, suggesting that membrane potential may be a universal mechanism governing ferroptosis. Together, our findings reveal that ferroptosis is determined by chloride ions.