iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4

Nat Commun. 2021 Jun 15;12(1):3644. doi: 10.1038/s41467-021-23902-6.


Here, we identify iPLA2β as a critical regulator for p53-driven ferroptosis upon reactive oxygen species (ROS)-induced stress. The calcium-independent phospholipase iPLA2β is known to cleave acyl tails from the glycerol backbone of lipids and release oxidized fatty acids from phospholipids. We found that iPLA2β-mediated detoxification of peroxidized lipids is sufficient to suppress p53-driven ferroptosis upon ROS-induced stress, even in GPX4-null cells. Moreover, iPLA2β is overexpressed in human cancers; inhibition of endogenous iPLA2β sensitizes tumor cells to p53-driven ferroptosis and promotes p53-dependent tumor suppression in xenograft mouse models. These results demonstrate that iPLA2β acts as a major ferroptosis repressor in a GPX4-independent manner. Notably, unlike GPX4, loss of iPLA2β has no obvious effect on normal development or cell viability in normal tissues but iPLA2β plays an essential role in regulating ferroptosis upon ROS-induced stress. Thus, our study suggests that iPLA2β is a promising therapeutic target for activating ferroptosis-mediated tumor suppression without serious toxicity concerns.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A549 Cells
  • Animals
  • Cell Line, Tumor
  • Cell Survival
  • Disease Models, Animal
  • Fatty Acids / metabolism
  • Female
  • Ferroptosis / genetics
  • Ferroptosis / physiology*
  • Group VI Phospholipases A2 / genetics
  • Group VI Phospholipases A2 / metabolism*
  • Humans
  • Mice
  • Mice, Nude
  • Phospholipid Hydroperoxide Glutathione Peroxidase / genetics
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism*
  • Phospholipids
  • Reactive Oxygen Species / metabolism
  • Tumor Suppressor Protein p53 / metabolism*
  • Xenograft Model Antitumor Assays


  • Fatty Acids
  • Phospholipids
  • Reactive Oxygen Species
  • TP53 protein, human
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • glutathione peroxidase 4, mouse
  • Group VI Phospholipases A2
  • Pla2g6 protein, mouse