Phospholipase PAFAH2 Mediates Ferroptosis Surveillance and Lipid Remodeling to Promote Resistance in KEAP1 Mutant Cancers

Although Ferroptosis resistance is prevalent among many Cancer cell types, precisely how Ferroptosis surveillance mechanisms are induced remains elusive due to the heterogeneity of the cellular mutational status and metabolic states. Here, we find that Phospholipase PAFAH2 regulates Ferroptosis through its unique ability to specifically detoxify membrane-bound oxidized Phospholipids in KEAP1 mutant and NRF2-active Cancer cells. We show that the genetic or chemical perturbation of PAFAH2 is sufficient to sensitize KEAP1 mutant lung adenocarcinoma cells to Ferroptosis. Lipidomic analyses reveal that PAFAH2 inhibition shifts the cellular lipidome to a distinctly Ferroptosis state characterized by the enrichment of key Phospholipids previously identified to be important in Ferroptosis, like ether-linked phosphatidylethanolamines. Finally, we comparatively assessed the antitumor efficacy of PAFAH2 inhibitor monotherapy versus cotreatment with a nanoparticle-stabilized GPX4 inhibitor formulation. Our findings support that the broad applicability of PAFAH2 inhibition can be used in Ferroptosis induction and abrogation of Ferroptosis resistance across Cancer types.