Scheme 1. LDE detoxification failure is a critical stage of ferroptotic cell death. Putative pathway linking LOOH accumulation in ferroptosis to LDE/truncated PL accumulation and to membrane permeabilization. Induction of ferroptosis leads to LOOH accumulation via lipid peroxidation. LOOH breakdown produces downstream LDE and truncated PL formation. Increased LDE production overwhelms or inhibits the two-step LDE detoxification pathway, leading to amplified cellular LDE accumulation. Several critical ferroptosis antagonist regulatory proteins including FSP1 and iPLA2β are susceptible to alkylation. Putative inactivation of FSP1 and iPLA2β, among other proteins, following LDE alkylation would remove inhibition of lipid peroxidation and increase retention of membrane LOOHs, respectively, leading to increased LOOH breakdown products in a positive feedback loop. Eventually, the level of truncated PLs reaches a critical concentration leading to membrane permeabilization.