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

Here, we identify iPLA2 beta as a critical regulator for p53-driven ferroptosis upon reactive oxygen species (ROS)-induced stress. The calcium-independent phospholipase iPLA2 beta is known to cleave acyl tails from the glycerol backbone of lipids and release oxidized fatty acids from phospholipids. We found that iPLA2 beta -mediated detoxification of peroxidized lipids is sufficient to suppress p53-driven ferroptosis upon ROS-induced stress, even in GPX4-null cells. Moreover, iPLA2 beta is overexpressed in human cancers; inhibition of endogenous iPLA2 beta sensitizes tumor cells to p53-driven ferroptosis and promotes p53-dependent tumor suppression in xenograft mouse models. These results demonstrate that iPLA2 beta acts as a major ferroptosis repressor in a GPX4-independent manner. Notably, unlike GPX4, loss of iPLA2 beta has no obvious effect on normal development or cell viability in normal tissues but iPLA2 beta plays an essential role in regulating ferroptosis upon ROS-induced stress. Thus, our study suggests that iPLA2 beta is a promising therapeutic target for activating ferroptosis-mediated tumor suppression without serious toxicity concerns. p53 is able to induce ferroptosis in response to reactive oxygen species (ROS)-induced stress and suppresses tumour growth. Here, the authors show that iPLA2 beta suppresses p53-medated ferroptosis by cleaving and detoxifying peroxidized lipids and that this is independent of canonical ferroptosis regulator GPX4.

Automated summary

The study identifies iPLA2 beta as a critical regulator for p53-driven ferroptosis independent of GPX4. Loss of iPLA2 beta does not have obvious effect on normal cells, but it plays an essential role in regulating ferroptosis upon ROS-induced stress. iPLA2 beta is a promising therapeutic target for activating ferroptosis-mediated tumor suppression without serious toxicity concerns.