Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture

Ferroptosis is a regulated form of necrotic cell death that is caused by the accumulation of oxidized phospholipids, leading to membrane damage and cell lysis^1,2. Although other types of necrotic death such as pyroptosis and necroptosis are mediated by active mechanisms of execution^3-6, ferroptosis is thought to result from the accumulation of unrepaired cell damage¹. Previous studies have suggested that ferroptosis has the ability to spread through cell populations in a wave-like manner, resulting in a distinct spatiotemporal pattern of cell death^7,8. Here we investigate the mechanism of ferroptosis execution and discover that ferroptotic cell rupture is mediated by plasma membrane pores, similarly to cell lysis in pyroptosis and necroptosis^3,4. We further find that intercellular propagation of death occurs following treatment with some ferroptosis-inducing agents, including erastin^2,9 and C' dot nanoparticles⁸, but not upon direct inhibition of the ferroptosis-inhibiting enzyme glutathione peroxidase 4 (GPX4)¹⁰. Propagation of a ferroptosis-inducing signal occurs upstream of cell rupture and involves the spreading of a cell swelling effect through cell populations in a lipid peroxide- and iron-dependent manner.