A Disintegrin and Metalloproteinase-8 Protects Against Erastin-Induced Neuronal Ferroptosis via Activating Nrf2/HO-1/FTH1 Signaling Pathway,Molecular Neurobiology

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A Disintegrin and Metalloproteinase-8 Protects Against Erastin-Induced Neuronal Ferroptosis via Activating Nrf2/HO-1/FTH1 Signaling Pathway
Molecular Neurobiology ( IF 4.6 ) Pub Date : 2023-11-23 , DOI: 10.1007/s12035-023-03782-1
Zhanyang Qian _{1,

2} , Qinyang Zhang _{1,

3} , Pengfei Li _{1,

4} , Yang Li _{1,

5} , Yanan Zhang ₁ , Rulin Li _{1,

3} , Tianyu Zhao _{1,

3} , Mingjie Xia ₆ , Yongyi Chen ₇ , Xin Hong ₂

Affiliation

Ferroptosis is a type of iron-dependent programmed cell death caused by the imbalance between oxidants and antioxidants. A disintegrin and metalloproteinase-8 (ADAM8) is a metalloproteinase that mediates cell adhesion, cell migration, and proteolytic activity. However, the molecular mechanism of ADAM8 regulating ferroptosis after neural disorder is unclear, especially in the neuron. In the present study, we identified the protective role of ADAM8 in Erastin-induced ferroptosis in vitro of the HT22 cells. It was found that overexpression of ADAM8 resulted in upregulated expression of GPX4 and FTH1 along with the decreased reactive oxygen species (ROS) production and reduced neuronal death; however, knockdown of ADAM8 resulted in an opposite. Mechanically, using the Nrf2 activator NK-252 and inhibitor nrf2-IN-1, we dmonstrated that ADAM8 regulates Erastin-mediated neuronal ferroptosis via activating the Nrf2/HO-1/FTH1 signaling pathway. In conclusion, the current study suggested that ADAM8 inhibited Erastin-induced neuronal ferroptosis through activating the Nrf2/HO-1/FTH1 signaling pathway, playing a protective role in vitro of the HT22 cell line. ADAM8 may be a promising and feasible target for neuronal survival in diseases of neural disorder.

Graphical Abstract

中文翻译：

解整合素和金属蛋白酶-8 通过激活 Nrf2/HO-1/FTH1 信号通路防止 Erastin 诱导的神经元铁死亡

铁死亡是一种由氧化剂和抗氧化剂之间不平衡引起的铁依赖性程序性细胞死亡。解整合素和金属蛋白酶 8 (ADAM8) 是一种介导细胞粘附、细胞迁移和蛋白水解活性的金属蛋白酶。然而，ADAM8在神经紊乱后调节铁死亡的分子机制尚不清楚，尤其是在神经元中。在本研究中，我们确定了 ADAM8 在体外 Erastin 诱导的 HT22 细胞铁死亡中的保护作用。研究发现，ADAM8 的过度表达会导致 GPX4 和 FTH1 的表达上调，同时活性氧 (ROS) 的产生减少，神经元死亡减少；然而，ADAM8 的敲除结果却相反。在机械方面，使用 Nrf2 激活剂 NK-252 和抑制剂 nrf2-IN-1，我们证明 ADAM8 通过激活 Nrf2/HO-1/FTH1 信号通路来调节 Erastin 介导的神经元铁死亡。总之，目前的研究表明ADAM8通过激活Nrf2/HO-1/FTH1信号通路抑制Erastin诱导的神经元铁死亡，在体外对HT22细胞系发挥保护作用。 ADAM8 可能是神经紊乱疾病中神经元存活的一个有前途且可行的靶标。

图解摘要

更新日期：2023-11-23

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