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Nrf2 Signaling Pathway: Focus on Oxidative Stress in Spinal Cord Injury

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Abstract

Spinal cord injury (SCI) is a serious, disabling injury to the central nervous system that can lead to motor, sensory, and autonomic dysfunction below the injury plane. SCI can be divided into primary injury and secondary injury according to its pathophysiological process. Primary injury is irreversible in most cases, while secondary injury is a dynamic regulatory process. Secondary injury involves a series of pathological events, such as ischemia, oxidative stress, inflammatory events, apoptotic pathways, and motor dysfunction. Among them, oxidative stress is an important pathological event of secondary injury. Oxidative stress causes a series of destructive events such as lipid peroxidation, DNA damage, inflammation, and cell death, which further worsens the microenvironment of the injured site and leads to neurological dysfunction. The nuclear factor erythrocyte 2–associated factor 2 (Nrf2) is considered to be a key pathway of antioxidative stress and is closely related to the pathological process of SCI. Activation of this pathway can effectively inhibit the oxidative stress process and promote the recovery of nerve function after SCI. Therefore, the Nrf2 pathway may be a potential therapeutic target for SCI. This review deeply analyzed the generation of oxidative stress in SCI, the role and mechanism of Nrf2 as the main regulator of antioxidant stress in SCI, and the influence of cross-talk between Nrf2 and related pathways that may be involved in the pathological regulation of SCI on oxidative stress, and summarized the drugs and other treatment methods based on Nrf2 pathway regulation. The objective of this paper is to provide evidence for the role of Nrf2 activation in SCI and to highlight the important role of Nrf2 in alleviating SCI by elucidating the mechanism, so as to provide a theoretical basis for targeting Nrf2 pathway as a therapy for SCI.

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Data Availability

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Abbreviations

3′UTR:

3′-Untranslated region

ARE:

Antioxidant response element

ATP:

Adenosine triphosphate

BMSC:

Bone marrow mesenchymal stem cell

CAT:

Catalase

CHD6:

Chromatin domain helicase DNA binding protein 6

CREB:

Cyclic AMP response element binding protein

ERKs:

Extracellular signal–regulated kinases

GDF15:

Growth and differentiation factor 15

GPx:

Glutathione peroxidase

GSH:

Glutathione

GSK-3β:

Glycogen synthase kinase-3β

GST:

Glutathione S-transferase

HO-1:

Heme oxygenase 1

HRD1:

HMG-CoA reductase–degrading protein 1

HSP70:

Heat shock protein 70

JNK:

C-Jun NH2-terminal protein kinase

Keap1:

Kelch-like epichlorohydrin–associated protein 1

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MDA:

Malondialdehyde

MG-Exos:

Microglia-derived exosomes

mPTP:

Mitochondrial permeability transition pore

NADPH:

Nicotinamide adenine dinucleotide phosphate

ncRNA:

Non-coding RNA

NF-κB:

Nuclear factor kappa B

NOX2:

Nicotinamide adenine dinucleotide phosphate oxidation 2

NQO1:

Quinone oxidoreductase

Nrf2:

Nuclear factor erythrocyte 2–associated factor 2

PI3K:

Phosphatidylinositol 3-kinase

PKC:

Protein kinase C

RARa:

Retinoic acid receptor a

RelA:

Protein called p65

rhEPO:

Recombinant human erythropoietin

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

RXRa:

Retinoid X receptor a

SCI:

Spinal cord injury

SET8:

SET domain protein 8

SOD:

Superoxide dismutase

TGF-β:

Transforming growth factor-β

XO:

Xanthine oxidase

β-TrCP:

Beta-transducin repeat-containing protein

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Funding

This work is supported by funding of the Science and Technology planning project of Jiangxi provincial health commission, China (No.202310747).

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Author notes

  1. Chun-lin Xiao and Hong-tong Lai contributed equally.

Authors and Affiliations

  1. Gannan Medical University, 1 Harmony Avenue, Rongjiang New District, Ganzhou, Jiangxi Province, 341000, People’s Republic of China

    Chun-lin Xiao, Hong-tong Lai, Wu-yang Liu & Kai Zhao

  2. Department of Orthopaedics, Frist Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province, 341000, People’s Republic of China

    Chun-lin Xiao, Hong-tong Lai, Wu-yang Liu & Kai Zhao

  3. Hospital 908, Joint Logistics Support Force, 1028 Jinggangshan Avenue, Qingyunpu District, Nanchang City, Jiangxi Province, 330001, People’s Republic of China

    Jiang-jun Zhou

  4. Department of Spine Surgery, Yingtan People’s Hospital, 116 Shengli West Road, Yuehu District, Yingtan City, Jiangxi Province, 335000, People’s Republic of China

    Min Zhao

Authors
  1. Chun-lin Xiao
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  2. Hong-tong Lai
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  3. Jiang-jun Zhou
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  4. Wu-yang Liu
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  5. Min Zhao
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  6. Kai Zhao
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Contributions

Chun-lin Xiao drafted the manuscript; Chun-lin Xiao and Hong-tong Lai wrote the manuscript; Min Zhao and Kai Zhao conceived and designed the review; Jiang-jun Zhou and Wu-yang Liu assisted in the preparation of the charts and tables. All authors read the manuscript and approved the submitted version.

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Correspondence to Min Zhao or Kai Zhao.

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Xiao, Cl., Lai, Ht., Zhou, Jj. et al. Nrf2 Signaling Pathway: Focus on Oxidative Stress in Spinal Cord Injury. Mol Neurobiol 62, 2230–2249 (2025). https://doi.org/10.1007/s12035-024-04394-z

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  • DOI: https://doi.org/10.1007/s12035-024-04394-z

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