Ethyl carbamate triggers ferroptosis in liver through inhibiting GSH synthesis and suppressing Nrf2 activation.
Ethyl carbamate triggers ferroptosis in liver through inhibiting GSH synthesis and suppressing Nrf2 activation.
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氨基甲酸乙酯通过抑制 GSH 合成和抑制 Nrf2 激活引发肝脏铁死亡
DOI：
10.1016/j.redox.2022.102349
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发表时间：
2022-07
期刊：
影响因子：
11.4
通讯作者：
Chen, Wei
中科院分区：
文献类型：
--
作者：
Xu, Yang;Li, Yuting;Li, Jiaxin;Chen, Wei
人类不可避免地会通过食用发酵食品和饮料而接触到氨基甲酸乙酯。EC是一种环境毒素，可引起氧化应激介导的严重毒性，但其潜在机制尚不清楚。铁凋亡是一种新发现的ROS介导的非凋亡性细胞死亡，其特征是铁积累和脂质过度氧化。在这项研究中，我们首次发现EC触发肝细胞铁凋亡，通过检测细胞活力，GSH，GPX 4和铁蛋白水平下降，以及铁和MDA含量增加。铁凋亡抑制剂ferrostatin-1（Fer-1）预处理挽救了铁凋亡损伤，表明铁凋亡是EC引起的细胞死亡的关键。此外，GSH合成前体N-乙酰半胱氨酸显示出显着的抗铁凋亡的特性，我们认为，GSH耗竭可能是铁凋亡EC暴露下的主要原因。EC触发的GSH消耗主要依赖于通过抑制SLC 7A 11和GCLC表达来抑制GSH合成。值得注意的是，EC通过抑制磷酸化修饰和核转位来阻断Nrf 2活化，这进一步导致铁凋亡的发生。我们还观察到EC诱导的Balb/c小鼠肝脏功能障碍和炎症，伴随氧化应激，铁凋亡和Nrf 2信号转导下调，Fer-1和tBHQ预处理可有效逆转。总之，我们的研究表明，铁凋亡是EC引起的毒性的新机制，这是由于Nrf 2失活和GSH耗尽。氨基甲酸乙酯（EC）引起L02细胞和肝组织的铁凋亡。GSH耗竭是EC诱导的铁凋亡细胞死亡的关键。EC暴露阻断了GSH合成相关途径。Nrf 2信号转导的失活参与了EC触发的铁凋亡。
Humans are inevitably exposed to ethyl carbamate (EC) via consumption of fermented food and beverages. EC, known as an environmental toxin, can cause oxidative stress-mediated severe toxicity, but the underlying mechanisms remain unveiled. Ferroptosis is a newly identified ROS-mediated non-apoptotic cell death characterized by iron accumulation and excessive lipid oxidation. In this study, we first found that EC triggered ferroptosis in liver cells by detection of decreased cell viability, GSH, GPX4 and Ferritin levels, as well as increased iron and MDA contents. Ferroptosis inhibitor ferrostatin-1 (Fer-1) pretreatment rescued ferroptotic damage, indicating that ferroptosis was critical for EC-caused cell death. Furthermore, GSH synthesis precursor N-acetylcysteine displayed significant anti-ferroptotic properties and we suggested that GSH depletion might be the main cause of ferroptosis under EC exposure. EC-triggered GSH depletion mainly depended on suppressed GSH synthesis via inhibition of SLC7A11 and GCLC expressions. Notably, EC blocked Nrf2 activation by repression of phosphorylation modification and nuclear translocation, which further resulted in ferroptosis occurrence. We also observed EC-induced liver dysfunction and inflammation, accompanied with oxidative stress, ferroptosis and downregulated Nrf2 signaling in Balb/c mice, which could be effectively reversed by Fer-1 and tBHQ pretreatment. Together, our study indicated that ferroptosis is a new mechanism for EC-caused toxicity, which was attributed to Nrf2 inactivation and GSH depletion. Ethyl carbamate (EC) caused ferroptosis in L02 cells and liver tissues. GSH depletion was critical for EC-induced ferroptotic cell death. EC exposure blocked GSH synthesis-related pathways. Inactivation of Nrf2 signaling was involved in EC-triggered ferroptosis.
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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：
--
作者：
Ayala A;Muñoz MF;Argüelles S
通讯作者：
Argüelles S
DOI：
10.1016/s0165-1218(96)00160-7
发表时间：
1997-04-24
影响因子：
1.9
作者：
Hubner, P;Groux, PM;Luthy, J
通讯作者：
Luthy, J
影响因子：
8.8
作者：
Hughes, Mark M.;Hooftman, Alexander;O'Neill, Luke A. J.
通讯作者：
O'Neill, Luke A. J.
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M