Novel third-generation ferrostatins protect against acute iron poisoning-induced organ injury

Ferroptosis is an iron dependent form of necrosis, involved in different pathologies such as kidney failure and neurodegenerative diseases. Glutathione peroxidase 4 (GPX4) is the central enzyme protecting the cell from ferroptosis. High-throughput screening led to the discovery of ferrostatin-1 (Fer-1) as a potent in vitro inhibitor of ferroptosis. In vivo however, the molecule suffers from instability. Therefore, we developed ferrostatin-analogues with improved solubility and in vivo stability. To verify their in vivo efficacy, we established an acute mouse model of iron poisoning-induced organ injury. Both an excess of the natural ferroptosis inhibitor vitamin E in the feed and overexpression of GPX4 have a protective effect on this iron poisoning model, indicating it is a valuable experimental model for ferroptosis-induced organ injury. Interestingly, our novel ferrostatin analogues effectively decrease several markers for organ injury after iron poisoning. Conclusively, 1) ferroptosis is a detrimental factor in acute iron poisoning, 2) our novel ferrostatin-analogues reduce the severity of organ injury due to acute iron poisoning, and 3) our third generation of ferrostatin-analogues might represent potential leads for the treatment of ferroptosis-driven pathologies.