GPX4-Regulated Ferroptosis Mediates S100-Induced Experimental Autoimmune Hepatitis Associated with the Nrf2/HO-1 Signaling Pathway.
GPX4-Regulated Ferroptosis Mediates S100-Induced Experimental Autoimmune Hepatitis Associated with the Nrf2/HO-1 Signaling Pathway.
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Gpx4调节的铁下垂介导S100诱导的与Nrf2/HO-1信号通路相关的实验性自身免疫性肝炎
DOI：
10.1155/2021/6551069
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发表时间：
2021
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Zhu L;Chen D;Zhu Y;Pan T;Xia D;Cai T;Lin H;Lin J;Jin X;Wu F;Yu S;Zhu K;Xu L;Chen Y
自身免疫性肝炎（AIH）是肝脏的炎性自身免疫性疾病。由活性氧自由基引发的氧化应激是许多肝脏疾病发病机制的共同病理生理基础，而铁凋亡与活性氧的毒性蓄积有关。负责铁加工和脂质过氧化机制的信号转导途径被认为是导致铁凋亡的原因。然而，调节铁凋亡的具体机制仍不清楚。本研究的目的是确定可能的效应功能的铁，谷胱甘肽过氧化物酶4（GPX 4）的调节的基础上，在S100诱导的自身免疫性肝炎小鼠模型和肝细胞损伤模型。采用S100肝抗原诱导的AIH小鼠模型，使用蛋白质印迹法检测铁蛋白生物标志物。S100诱导的AIH模型组COX 2和ACSL 4表达上调，GPX 4和FTH 1表达下调（P < 0.05）。在给予ferrostatin-1后，COX 2、ACSL 4、GPX 4和FTH 1的表达谱得到恢复。另外，与非ferrostatin-1治疗组相比，ferrostatin-1治疗组S100诱导的AIH模型小鼠的Nrf 2和HO-1水平下调（P < 0.05）。此外，在AIH模型小鼠中，当使用AAV 8构建体沉默肝脏特异性GPX 4时，COX 2和ACSL 4水平显著上调，FTH 1显著下调。这些数据表明，铁凋亡的抑制显着改善AIH对核因子E2相关因子2（Nrf 2）/血红素加氧酶-1（HO-1）信号通路的影响，铁凋亡可能作为引发剂或中间介质导致AIH。
Autoimmune hepatitis (AIH) is an inflammatory autoimmune disease of the liver. Oxidative stress triggered by reactive oxygen radicals is a common pathophysiological basis for the pathogenesis of many liver diseases, and ferroptosis is associated with the toxic accumulation of reactive oxygen species. The signaling transduction pathways responsible for iron processing and lipid-peroxidation mechanisms are believed to drive ferroptosis. However, the specific mechanisms regulating ferroptosis remain unclear. The aims of this investigation were to identify the possible effector functions of ferroptosis, based on glutathione peroxidase 4 (GPX4) regulation in an S100-induced autoimmune hepatitis mouse model and hepatocyte injury models. The S100 liver antigen-induced AIH mouse model was used to detect ferroptotic biomarkers using western blotting. Upregulated levels of cyclooxygenase2 (COX2) and Acyl-Coenzyme A synthase long-chain family member 4 (ACSL4) were observed in the S100-induced AIH model group, while levels of GPX4 and ferritin heavy chain 1 (FTH1) were downregulated (P < 0.05). The expression profiles of COX2, ACSL4, GPX4, and FTH1 were restored following the administration of ferrostatin-1. In addition, Nrf2 and HO-1 levels in the S100-induced AIH model mice after treatment with ferrostatin-1 were downregulated compared to the nonferrostatin-1-treated S100-induced AIH model mice (P < 0.05). Moreover, COX2 and ACSL4 levels were significantly upregulated, with significant FTH1 downregulation, in the AIH model mice when liver-specific GPX4 was silenced using AAV8 constructs. These data indicate that inhibition of ferroptosis significantly ameliorated the influence of AIH on the Nuclear factor E2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway, and that ferroptosis may act as an initiator or intermediate mediator leading to AIH.
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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
DOI：
10.1038/nrrheum.2015.169
发表时间：
2016-01
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
Kalliolias GD;Ivashkiv LB
通讯作者：
Ivashkiv LB
影响因子：
4
作者：
Hegazy, Ahmad K.;Mohamed, Amal A.;Al-Sobeai, Sanad
通讯作者：
Al-Sobeai, Sanad
影响因子：
24.5
作者：
Miyazaki, E;Kato, J;Niitsu, Y
通讯作者：
Niitsu, Y
影响因子：
11.2
作者：
Shi, J;Zheng, DX;Xu, RA
通讯作者：
Xu, RA