Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal

Nat Chem Biol. 2021 Apr;17(4):465-476. doi: 10.1038/s41589-020-00734-x. Epub 2021 Feb 4.


Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2β (iPLA2β, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2β averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2β expression and a PD-relevant phenotype. Thus, iPLA2β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonate 15-Lipoxygenase / metabolism
  • Disease Models, Animal
  • Female
  • Ferroptosis / physiology*
  • Group VI Phospholipases A2 / metabolism*
  • Group VI Phospholipases A2 / physiology
  • Humans
  • Iron / metabolism
  • Leukotrienes / metabolism
  • Lipid Metabolism / physiology
  • Lipid Peroxides / metabolism
  • Lipids / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidation-Reduction
  • Parkinson Disease / metabolism
  • Phosphatidylethanolamine Binding Protein / metabolism
  • Phospholipases / metabolism
  • Phospholipids / metabolism
  • Rats
  • Rats, Inbred Lew


  • Leukotrienes
  • Lipid Peroxides
  • Lipids
  • PEBP1 protein, human
  • Phosphatidylethanolamine Binding Protein
  • Phospholipids
  • 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid
  • Iron
  • Arachidonate 15-Lipoxygenase
  • Phospholipases
  • Group VI Phospholipases A2
  • Pla2g6 protein, mouse