Ji-Yoon Lee^a,b,1, Miso Nam^c,1,2, Hye Young Son^d,1, Kwangbeom Hyun^a, Seo Young Jang^c,e, Jong Woo Kim^b,f,Min Wook Kim^b, Youngae Jung^c, Eunji Jang^g, Seon-Jin Yoon^h, Jungeun Kim^g, Jihye Kim^g, Jinho Seoⁱ, Jeong-Ki Min^e,j, Kyoung-Jin Oh^b,f, Baek-Soo Han^f,k, Won Kon Kim^b,f, Kwang-Hee Bae^b,f,l, Jaewhan Song^m, Jaehoon Kim^a, Yong-Min Huh^d,g,l,n,3, Geum-Sook Hwang^c,e,3, Eun-Woo Lee^b,3, and Sang Chul Lee^b,3

^aDepartment of Biological Sciences, Korea Advanced Institute of Science and Technology, 34141 Daejeon, Korea; ^bMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141 Daejeon, Korea; ^cIntegrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, 03759 Seoul, Korea; ^dSeverance Biomedical Science Institute, Yonsei University College of Medicine, 03722 Seoul, Korea; ^eDepartment of Chemistry and Nano Science, Ewha Woman’s University, 03760 Seoul, Korea; ^fDepartment of Functional Genomics, University of Science and Technology, 34141 Daejeon, Korea; ^gMediBio-Informatics Research Center, Novomics Co., Ltd., 07217 Seoul, Korea; ^hDepartment of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 03722 Seoul, Korea; ⁱEnvironmental Diseases Research Center, KRIBB, 34141 Daejeon, Korea; ^jBiotherapeutics Translational Research Center, KRIBB, 34141 Daejeon, Korea; ^kBiodefense Research Center, KRIBB, 34141 Daejeon, Korea; ^lYonsei University Health System (YUHS)-KRIBB Medical Convergence Research Institute, 03722 Seoul, Korea; ^mDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 03722 Seoul, Korea; and ⁿDepartment of Radiology, Severance Hospital, Yonsei University College of Medicine, 03722 Seoul, Korea

¹J.-Y.L., M.N., and H.Y.S. contributed equally to this work.
²Present address: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
³To whom correspondence may be addressed. 

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

ferroptosis, lipid peroxidation, ELOVL5, FADS1, arachidonic acid