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 damage(1). 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 nanoparticles(8), 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. Two complementary studies from the laboratories of Riegman et al. and Katikaneni et al., respectively, identify a key role for controlled wave-like propagation of lipid peroxide signalling during wound detection in vivo and in ferroptotic cell death.