The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism

Mihee Oh, Seo Young Jang, Ji-Yoon Lee, Jong Woo Kim, Youngae Jung, Jiwoo Kim, Jinho Seo, Tae-Su Han, Eunji Jang, Hye Young Son, Dain Kim, Min Wook Kim, Jin-Sung Park, Kwon-Ho Song, Kyoung-Jin Oh, Won Kon Kim, Kwang-Hee Bae, Yong-Min Huh, Soon Ha Kim, Doyoun Kim, Baek-Soo Han (), Sang Chul Lee (), Geum-Sook Hwang () and Eun-Woo Lee ()
Additional contact information
Mihee Oh: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Seo Young Jang: Western Seoul Center, Korea Basic Science Institute
Ji-Yoon Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Jong Woo Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Youngae Jung: Western Seoul Center, Korea Basic Science Institute
Jiwoo Kim: Drug Discovery Platform Research Center, Korea Research Institute of Chemical Technology (KRICT)
Jinho Seo: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Tae-Su Han: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Eunji Jang: Novomics Co., Ltd.
Hye Young Son: YUHS-KRIBB Medical Convergence Research Institute
Dain Kim: Western Seoul Center, Korea Basic Science Institute
Min Wook Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Jin-Sung Park: MitoImmune Therapeutics Inc.
Kwon-Ho Song: Daegu Catholic University School of Medicine
Kyoung-Jin Oh: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Won Kon Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Kwang-Hee Bae: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Yong-Min Huh: Novomics Co., Ltd.
Soon Ha Kim: MitoImmune Therapeutics Inc.
Doyoun Kim: Drug Discovery Platform Research Center, Korea Research Institute of Chemical Technology (KRICT)
Baek-Soo Han: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Sang Chul Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Geum-Sook Hwang: Western Seoul Center, Korea Basic Science Institute
Eun-Woo Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.

Date: 2023
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DOI: 10.1038/s41467-023-41462-9

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