Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture

Ferroptosis is a lipid peroxide-dependent form of cell death that occurs in degenerative conditions and may be leveraged for cancer therapy. Although numerous regulators are known to control its cell-autonomous execution, ferroptosis also has a collective property that involves propagation between cells, and this regulation has remained more obscure. Different modes of ferroptosis induction involving inhibition of the anti-ferroptotic enzyme GPX4 or depletion of glutathione can impact the collective death response differently, but the mechanisms underlying "single-cell" versus "propagative" ferroptosis are not well understood. Here, we discover significant lysosome rupture occurring during propagative ferroptosis and identify glutathione depletion as sufficient to convert GPX4 inhibition from an individual-cell response to a collective response. We find that induction of single-cell ferroptosis involves heterogeneous death profiles, with necrosis and apoptosis occurring in parallel within cell populations. These findings identify factors that control propagation and underscore lysosomes as critical to the execution of ferroptosis.