Plasticity of ether lipids promotes ferroptosis susceptibility and evasion

Ferroptosis, an iron-dependent, non-apoptotic cell death program, is involved in a variety of degenerative diseases and represents a targetable vulnerability in certain cancers. The ferroptosis-susceptible cell-state can either preexist in cells arising from certain lineages or be acquired during cell-state transitions. Precisely how ferroptosis susceptibility is dynamically regulated remains poorly understood. Using genome-wide CRISPR/Cas9 suppressor screens, we identify a key role for peroxisome–ether phospholipid genes in driving ferroptosis susceptibility and evasion in ovarian cancer. Ovcar8 CRISPR library infected cells treated with escalating doses of RSL3 (Selleckchem) for 4 days each: 0.5 μM, 1 μM, and 2μM. 1×10^7 cells each were collected from the surviving population of RSL3-treated cells and an endpoint-matched untreated population for downstream sequencing analysis.