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

Delin Chen, Bo Chu, Xin Yang, Zhaoqi Liu, Ying Jin, Ning Kon, Raul Rabadan, Xuejun Jiang, Brent R. Stockwell and Wei Gu ()
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Delin Chen: Columbia University
Bo Chu: Columbia University
Xin Yang: Columbia University
Zhaoqi Liu: Columbia University
Ying Jin: Columbia University
Ning Kon: Columbia University
Raul Rabadan: Columbia University
Xuejun Jiang: Memorial Sloan-Kettering Cancer Center
Brent R. Stockwell: Columbia University
Wei Gu: Columbia University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23902-6

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