Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1.
Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1.
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DOI：
10.1038/s41467-021-22471-y
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发表时间：
2021-04-14
影响因子：
16.6
通讯作者：
Peterson JR
中科院分区：
文献类型：
--
作者：
Beatty A;Singh T;Tyurina YY;Tyurin VA;Samovich S;Nicolas E;Maslar K;Zhou Y;Cai KQ;Tan Y;Doll S;Conrad M;Subramanian A;Bayır H;Kagan VE;Rennefahrt U;Peterson JR
铁缺乏症与多不饱和酰基链氧化产生的脂质氢过氧化物有关。脂质过氧化氢被谷胱甘肽过氧化物酶4（GPX 4）还原，GPX 4抑制剂诱导铁凋亡。然而，用多不饱和脂肪酸触发癌细胞中的铁凋亡的治疗潜力是未知的。在这里，我们确定共轭亚油酸，包括α-桐酸（αESA）作为铁凋亡诱导剂。αESA不会改变GPX 4活性，但会掺入细胞脂质中，并促进各种癌细胞类型中的脂质过氧化和细胞死亡。α ESA触发的死亡由酰基辅酶A合成酶长链亚型1介导，可促进αESA掺入中性脂质（包括三酰基甘油）。干扰三酰甘油生物合成可抑制由αESA而非GPX 4抑制引发的铁凋亡。对小鼠口服天然富含αESA的桐油可限制肿瘤生长和转移，其转录变化与铁凋亡一致。总的来说，这些发现阐明了一种潜在的方法，以补充GPX 4抑制。脂质过氧化物酶GPX 4的抑制促进铁凋亡细胞死亡。在这里，作者确定了一种互补的方法，使用共轭亚麻酸，通过ACSL 1，DGAT 1/2和中性脂质引发脂质过氧化和铁凋亡。
Ferroptosis is associated with lipid hydroperoxides generated by the oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. Here, we identify conjugated linoleates including α-eleostearic acid (αESA) as ferroptosis inducers. αESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by αESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in αESA, to mice limits tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a potential approach to ferroptosis, complementary to GPX4 inhibition. Inhibition of the lipid peroxidase GPX4 promotes ferroptotic cell death. Here, the authors identify a complementary approach using conjugated linolenic fatty acids that trigger lipid peroxidation and ferroptosis via ACSL1, DGAT1/2, and neutral lipids.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
3.3
作者：
Grossmann, Michael E.;Mizuno, Nancy K.;Cleary, Margot P.
通讯作者：
Cleary, Margot P.
影响因子：
2.1
作者：
Conrad M;Friedmann Angeli JP
通讯作者：
Friedmann Angeli JP
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
4
作者：
Dixon SJ;Winter GE;Musavi LS;Lee ED;Snijder B;Rebsamen M;Superti-Furga G;Stockwell BR
通讯作者：
Stockwell BR