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

• Published in: Nature communications Vol. 12; no. 1; pp. 3644 - 15
• Main Authors: Chen, Delin, Chu, Bo, Yang, Xin, Liu, Zhaoqi, Jin, Ying, Kon, Ning, Rabadan, Raul, Jiang, Xuejun, Stockwell, Brent R., Gu, Wei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/89; 14/5; 631/67/2327; 631/80/82; 82/58; 82/83; A549 Cells; Animal models; Animals; Calcium; Cell Line, Tumor; Cell Survival; Cell viability; Detoxification; Disease Models, Animal; Fatty acids; Fatty Acids - metabolism; Female; Ferroptosis; Ferroptosis - genetics; Ferroptosis - physiology; Glycerol; Group VI Phospholipases A2 - genetics; Group VI Phospholipases A2 - metabolism; Humanities and Social Sciences; Humans; Lipid peroxidation; Lipids; Mice; Mice, Nude; multidisciplinary; Null cells; p53 Protein; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Phospholipids; Reactive oxygen species; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Toxicity; Tumor cells; Tumor suppression; Tumor Suppressor Protein p53 - metabolism; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• 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. p53 is able to induce ferroptosis in response to reactive oxygen species (ROS)-induced stress and suppresses tumour growth. Here, the authors show that iPLA2β suppresses p53-medated ferroptosis by cleaving and detoxifying peroxidized lipids and that this is independent of canonical ferroptosis regulator GPX4.