贫暴露通过ETHE1/P38-MAPK通路诱导了细胞中的铁亡
Feng Huang1, Wenrun Li1, Juan Li1
1State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University, Chongqing, 400038, China.
Archives of toxicology
|November 7, 2025
概括
急性缩暴露会通过铁亡引起损伤,这是一种细胞死亡途径,涉及铁的积累和线粒体功能障碍. 这项研究揭示了ETHE1下调和P38-MAPK激活是推动这种毒性的关键机制.
科学领域:
- 毒理学 毒理学 毒理学
- 细胞生物学 细胞生物学
- 生物化学 生化学
背景情况:
- 暴露于贫 (DU) 是一个重大的健康问题,可能导致脏损伤.
- 由于DU诱导的毒性,背后的确切机制尚未完全理解.
- 铁亡,一种受调节的细胞死亡形式,在各种有毒损伤中越来越多地得到了认可.
研究的目的:
- 为了研究铁灭菌在急性贫 (DU) 诱导的毒性中的作用.
- 为了阐明涉及DU诱导损伤的分子途径.
主要方法:
- 在Sprague-Dawley大鼠和HK-2细胞中建立了急性DU暴露模型.
- 评估了线粒体功能障碍,脂质过氧化和铁积累.
- 利用铁素-1 (Fer-1) 抑制铁灭.
- 研究了乙基马龙性脑病变1 (ETHE1) 和p38基激活蛋白激酶 (P38-MAPK) 信号传导的作用.
- 研究了核受体联合激活剂4 (NCOA4) 在费里丁菌中的参与.
主要成果:
- 暴露于DU引发了铁亡的特征,包括线粒体功能障碍,脂质过氧化和铁过载,这些特征被 Fer-1 逆转.
- ETHE1被确定为一个关键的DU目标;它的下调加剧了DU诱导的活性氧物种 (ROS) 和铁亡.
- 由DU触发的ROS激活了P38-MAPK通路,导致NCOA4介导的费里丁和随后的铁死.
- 抑制P38-MAPK或NCOA4减弱的DU诱导的铁灭.
结论:
- 急性DU暴露会通过降低ETHE1的调节引起毒性,从而导致线粒体ROS的产生.
- 激活的P38-MAPK信号传递促进NCOA4介导的费里丁,最终导致细胞铁亡.
- 这项研究揭示了一种新的DU诱导的损伤机制,涉及铁亡.
相关概念视频
01:16Necrosis
6.3K
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
6.3K
01:37The Unfolded Protein Response
6.2K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
6.2K
01:31Regulation of the Unfolded Protein Response
2.9K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.9K
01:46Electron Transport Chain: Complex I and II
18.4K
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
18.4K
01:07MAPK Signaling Cascades
7.8K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
7.8K