Nrf2 通过抑制 NCOA4 介导的噬铁蛋白作用防止软骨终板退化。

IF 8.3 2区 材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY
Zhenkai Ma, Hui Lu, Xuemin Feng, Ting Du, Jianhua Li, Qiang Zhang, Xindong Gu, Yuandong Shao, Xingzhi Jing, Cheng Su
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引用次数: 0

摘要

铁超载和铁变态反应与椎间盘变性(IDD)有关;然而,铁稳态的调节机制仍有待阐明。有报道称核因子红细胞2相关因子2(Nrf2)可调节细胞铁稳态,但其对IDD病理的影响及其作用机制仍有待进一步研究。本研究对软骨终板(CEP)中 Nrf2 的表达进行了免疫组化分析,结果表明,在 IDD 发病早期,CEP 中 Nrf2 的表达增加,而在 IDD 发病晚期,Nrf2 的表达减少。Western印迹分析结果表明,Nrf2激活不足可能会加重线粒体功能障碍和氧化应激,从而促进CEP软骨细胞变性和钙化。研究还发现,Nrf2参与了TNF-α诱导的CEP软骨细胞铁代谢功能障碍和铁变态反应。利用Nrf2小干扰RNA抑制Nrf2的表达,可增强核受体辅激活子4(NCOA4)介导的噬铁过程,增加亚铁离子含量,从而促进CEP软骨细胞的嗜铁细胞死亡和细胞外基质降解。此外,细胞铁浓度的降低可能会抑制 CEP 软骨细胞的铁嗜性以及 CEP 的变性和钙化。本研究强调了Nrf2/NCOA4轴在软骨细胞铁凋亡和IDD发病机制中的作用,从而表明激活Nrf2可能是治疗IDD的一种有前途的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Nrf2 protects against cartilage endplate degeneration through inhibiting NCOA4‑mediated ferritinophagy.
Iron overload and ferroptosis are associated with intervertebral disc degeneration (IDD); however, the mechanism underlying the regulation of iron homeostasis remains to be elucidated. Nuclear factor erythroid 2‑related factor 2 (Nrf2) has been reported to regulate cellular iron homeostasis; however, its impact on IDD pathology and the underlying mechanism of action requires further investigation. In the present study, immunohistochemistry analysis of Nrf2 expression in the cartilage endplate (CEP) was conducted and it was demonstrated that Nrf2 expression was increased in the CEP at the early stages of the development of IDD, whereas it was decreased at the late stages of the development of IDD. The results of western blot analysis indicated that the inadequate activation of Nrf2 may aggravate mitochondrial dysfunction and oxidative stress, thus promoting CEP chondrocyte degeneration and calcification. It was also revealed that Nrf2 was involved in TNF‑α‑induced CEP chondrocyte iron metabolism dysfunction and ferroptosis. Inhibition of Nrf2 expression using Nrf2 small interfering RNA could enhance the process of nuclear receptor coactivator 4 (NCOA4)‑mediated ferritinophagy and increase ferrous ion content, which may promote CEP chondrocyte ferroptotic cell death and extracellular matrix degradation. Furthermore, a decrease in cellular iron concentration may inhibit CEP chondrocyte ferroptosis, and CEP degeneration and calcification. The present study highlights the role of the Nrf2/NCOA4 axis in chondrocyte ferroptosis and IDD pathogenesis, thus suggesting that activation of Nrf2 may be a promising strategy for IDD treatment.
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来源期刊
ACS Applied Materials & Interfaces
ACS Applied Materials & Interfaces 工程技术-材料科学:综合
CiteScore
16.00
自引率
6.30%
发文量
4978
审稿时长
1.8 months
期刊介绍: ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.
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