Nrf2 protects against cartilage endplate degeneration through inhibiting NCOA4‑mediated ferritinophagy

Ma,Zhenkai; Lu,Hui; Feng,Xuemin; Du,Ting; Li,Jianhua; Zhang,Qiang; Gu,Xindong; Shao,Yuandong; Jing,Xingzhi; Su,Cheng

doi:10.3892/ijmm.2023.5339

Nrf2 protects against cartilage endplate degeneration through inhibiting NCOA4‑mediated ferritinophagy

Authors:
- Zhenkai Ma
- Hui Lu
- Xuemin Feng
- Ting Du
- Jianhua Li
- Qiang Zhang
- Xindong Gu
- Yuandong Shao
- Xingzhi Jing
- Cheng Su
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Affiliations: Department of Neurosurgery, Binzhou People's Hospital, Binzhou, Shandong 256600, P.R. China, Department of Endocrinology, Binzhou People's Hospital, Binzhou, Shandong 256600, P.R. China, Department of Medicine, Yidu Cloud (Beijing) Technology Co., Ltd., Beijing 100191, P.R. China, Department of Spine Surgery, Binzhou People's Hospital, Binzhou, Shandong 256600, P.R. China, Department of Spine Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250000, P.R. China
Published online on: December 7, 2023 https://doi.org/10.3892/ijmm.2023.5339
Article Number: 15
Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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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