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Ferroptosis is a newly characterized iron-dependent form of nonapoptotic regulated cell death triggered by lipid reactive oxygen species (LOOH).The dysregulation of ferroptosis is highly related to cancer,and the induction of ferroptosis is also proposed as a potential strategy for cancer therapy.Although several key regulators have been identified that are involved in ferroptosis,the molecular mechanism underlying this process remains largely unknown.Here,we report that Peroxiredoxin-6 (PRDX6) is a bona fide negative regulator of ferroptotic cell death.The knockdown of intracellular PRDX6 significantly enhances LOOH and ferroptotic cell death triggered by ferroptosis inducers (Erastin and RSL-3),which is correlated with the transcriptional activation of heme oxygenase-1.Moreover,overexpression of heme oxygenase-1 enhances both Erastin-and RSL-3-triggered LOOH,suggesting that hene oxygenase-1 mediates PRDX6 silencing-enhanced ferroptosis.More importantly,the application of a specific PRDX6 phospholipase A2 (iPLA2) inhibitor,M J-33,synergistically enhances the ferroptosis induced by Erastin,suggesting that PRDX6 removes LOOH through its iPLA2 activity.Thus,our findings reveal an essential role of PRDX6 in protecting cells against ferroptosis and provide a potential target to improve the antitumor activity of ferroptosis-based chemotherapy.