程序性细胞死亡
氧化应激
谷胱甘肽
化学
GPX4
毒性
活性氧
细胞凋亡
铁蛋白
脂质过氧化
生物化学
细胞生物学
生物
酶
超氧化物歧化酶
有机化学
谷胱甘肽过氧化物酶
作者
Yang Xu,Yuting Li,Jiaxin Li,Wei Chen
出处
期刊:Redox biology
[Elsevier]
日期:2022-07-01
卷期号:53: 102349-102349
被引量:67
标识
DOI:10.1016/j.redox.2022.102349
摘要
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.
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