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·2026
Methionine metabolism is linked with phospholipid and glutamine metabolism to drive ferroptosis
Jong Woo Kim, Seo Young Jang, Yeon Jin Roh, Yeajin Ju, Ju-Bin Kang, B. H. Park, Ji-Yoon Lee, Min Wook Kim, Byung Jun Jeong, Woosung Jung, Kyoung‐Jin Oh, Won Kon Kim, Baek-Soo Han, Kwang‐Hee Bae, Tackhoon Kim, Yun Pyo Kang, Hee Min Yoo, Chuna Kim, Scott J. Dixon, Dong Wook Choi, Geum-Sook Hwang, Eun‐Woo Lee
IF 6.9Cell Reports
초록

Ferroptosis is a lipid peroxidation-induced cell death mechanism that is regulated by amino acid metabolism. Cystine deprivation induces ferroptosis, but ferroptosis execution requires other amino acids. While methionine contributes to several metabolic pathways, including transsulfuration (TS), its role in ferroptosis remains controversial. Here, we report that methionine is required for ferroptosis triggered by cysteine deprivation. Notably, the TS pathway and methionine cycle in lung cancer cells are largely inactive, and methionine is instead funneled into polyamine synthesis via the methionine salvage route. Methionine depletion provokes metabolic shifts that dampen glutamine catabolism via the glutamine-methionine bi-cycle. Furthermore, methionine depletion alters phospholipid metabolism by promoting ACSL4 degradation, limiting polyunsaturated fatty acid (PUFA) incorporation into phospholipids. The methionine cycle intermediate S-adenosylmethionine (SAM) supplementation is sufficient to restore the perturbed metabolic state and ferroptosis sensitivity. Taken together, the results of this study highlight methionine as a key coordinator of ferroptosis through dynamic metabolic remodeling.

키워드
MetabolismGlutaminePhospholipidMethionineLipid metabolism
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IF / 인용수
6.9 / 0
게재 연도
2026

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