Nrf2 attenuates ferroptosis-mediated IIR-ALI by modulating TERT and SLC7A11.
Nrf2 attenuates ferroptosis-mediated IIR-ALI by modulating TERT and SLC7A11.
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Nrf2通过调节TERT和SLC7A11来减弱铁凋亡介导的IIR-ALI。
DOI：
10.1038/s41419-021-04307-1
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发表时间：
2021-10-29
影响因子：
9
通讯作者：
Jiang H
中科院分区：
文献类型：
--
作者：
Dong H;Xia Y;Jin S;Xue C;Wang Y;Hu R;Jiang H
急性肺损伤（acute lung injury，ALI）的死亡率约为50%，是世界危重病研究的热点。核因子红细胞2相关因子2（Nrf 2）是细胞内氧化稳态的关键调节剂，并作为抗氧化剂。Nrf 2相关的抗氧化应激与铁凋亡抑制密切相关。同时，端粒酶逆转录酶（TERT），端粒酶蛋白的催化部分，据报道，前往线粒体，以减轻ROS。在我们的研究中，我们发现在肠缺血/再灌注诱导的急性肺损伤（IIR-ALI）模型中，Nrf 2 −/−小鼠肺组织中的TERT显著减少。此外，MDA水平显着增加，而GSH和GPX 4水平急剧下降，在ALI模型。此外，在IIR模型中的II型肺泡上皮细胞中观察到典型相关的结构变化。我们进一步采用扫描透射X射线显微镜（STXM）检查细胞内的Fe水平和分布。根据我们的观察，大量的铁聚集体被发现在MLE-12细胞OGD/R（氧和葡萄糖剥夺/再灌注）诱导。此外，Nrf 2沉默显著降低了TERT和SLC 7A 11水平，并进一步加剧了细胞损伤。相反，TERT过表达细胞表现出SLC 7A 11水平的显著升高，从而抑制了铁凋亡。总的来说，这些数据表明Nrf 2可以通过调节TERT和SLC 7A 11水平来负调节铁凋亡。这项研究的结论为未来IIR-ALI治疗提供了新的候选药物。
Acute lung injury (ALI) carries a mortality rate of ~50% and is a hot topic in the world of critical illness research. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical modulator of intracellular oxidative homeostasis and serves as an antioxidant. The Nrf2-related anti-oxidative stress is strongly associated with ferroptosis suppression. Meanwhile, telomerase reverse transcriptase (TERT), the catalytic portion of the telomerase protein, is reported to travel to the mitochondria to alleviate ROS. In our study, we found that TERT was significantly reduced in lung tissue of Nrf2−/− mice in the model of intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI). In addition, MDA levels showed marked increase, whereas GSH and GPX4 levels fell drastically in ALI models. Moreover, typical-related structural changes were observed in the type II alveolar epithelial cells in the IIR model. We further employed the scanning transmission X-ray microscopy (STXM) to examine Fe levels and distribution within cells. Based on our observations, massive aggregates of Fe were found in the MLE-12 cells upon OGD/R (oxygen and glucose deprivation/reperfusion) induction. Additionally, Nrf2 silencing dramatically reduced TERT and SLC7A11 levels, and further exacerbated cellular injuries. In contrast, TERT-overexpressing cells exhibited marked elevation in SLC7A11 levels and thereby inhibited ferroptosis. Collectively, these data suggest that Nrf2 can negatively regulate ferroptosis via modulation of TERT and SLC7A11 levels. The conclusion from this study brings insight into new candidates that can be targeted in future IIR-ALI therapy.
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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：
11.4
作者：
Roh, Jong-Lyel;Kim, Eun Hye;Jang, Hyejin;Shin, Daiha
通讯作者：
Shin, Daiha
p62-Keap1-NRF2 通路的激活可防止肝细胞癌细胞中的铁死亡。
DOI：
10.1002/hep.28251
发表时间：
2016-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Sun X;Ou Z;Chen R;Niu X;Chen D;Kang R;Tang D
通讯作者：
Tang D
影响因子：
3.6
作者：
Lee H;Ko EH;Lai M;Wei N;Balroop J;Kashem Z;Zhang M
通讯作者：
Zhang M
影响因子：
2.2
作者：
Fantozzi, Evelyn Thais;Breithaupt-Faloppa, Ana Cristina;Tavares-de-Lima, Wothan
通讯作者：
Tavares-de-Lima, Wothan