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Mitochondria‑driven ferroptosis in intervertebral disc degeneration: A novel target in age‑related spinal diseases (Review)

  • Authors:
    • Yang Hou
    • Xiaolei Yang
    • Duorun Qiu
    • Lei Liu
    • Jiangang Shi
    • Yongfei Guo
  • View Affiliations / Copyright

    Affiliations: Department of Orthopedic Surgery, Changzheng Hospital, Shanghai 200003, P.R. China
    Copyright: © Hou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 88
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    Published online on: February 2, 2026
       https://doi.org/10.3892/etm.2026.13083
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Abstract

Ferroptosis, an iron‑dependent form of programmed cell death driven by lipid peroxidation and reactive oxygen species (ROS), has emerged as a key mechanism in the progression of intervertebral disc degeneration (IDD). Mitochondria serve a central role in this process by regulating iron metabolism, ROS production and energy homeostasis. In IDD, mitochondrial dysfunction leads to increased lipid ROS levels, decreased glutathione peroxidase 4 (GPX4) activity and impaired antioxidant defenses, contributing to extracellular matrix degradation and nucleus pulposus cell death. The present review summarizes the core molecular mechanisms underlying ferroptosis and highlights the mitochondrial pathways that mediate ferroptosis in IDD. Furthermore, the advances in mitochondria‑targeted therapeutic strategies are discussed, including antioxidants, iron chelators, GPX4 activators, mitophagy modulators and nanotechnology‑based interventions. These approaches provide promising avenues for preventing ferroptosis‑induced disc degeneration and preserving the viability of disc cells. Understanding the interplay between mitochondrial dysfunction and ferroptosis may offer novel insights for the development of precise and effective treatments for IDD.

View Figures

Figure 1

Mitochondria-mediated ferroptosis
promotes extracellular matrix degradation in intervertebral disc
degeneration. Mitochondrial dysfunction, triggered by iron overload
and oxidative stress, leads to the accumulation of MitoROS and the
activation of ferroptosis in nucleus pulposus cells (NPCs). Excess
iron accumulates through mechanisms such as TfR upregulation and
FTH1 downregulation, promoting lipid peroxidation and ROS
generation. These processes result in cell death and the subsequent
release of inflammatory mediators that exacerbate intervertebral
disc degeneration. Furthermore, mitochondrial dysfunction impairs
GPX4 activity, leading to reduced antioxidant capacity and
increased oxidative damage. This cascade of events ultimately
accelerates ECM degradation, contributing to the progression of
IDD. GPX4, glutathione peroxidase 4; ECM, extracellular matrix; NP,
nucleus pulposus; LPS, lipopolysaccharide; Tf, transferrin; Sirt3,
sirtuin 3; ROS, reactive oxygen species; GSH, glutathione; SCL7A11,
solute carrier family 7 member 11.

Figure 2

Therapeutic strategies targeting
mitochondrial dysfunction-induced ferroptosis in intervertebral
disc degeneration. SCL7A11, solute carrier family 7 member 11;
PINK1, PTEN-induced kinase 1; NCOA4, nuclear receptor coactivator
4; MitoQ, mitochondria-targeted coenzyme Q10; GPX4, GPX4,
glutathione peroxidase 4.
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Copy and paste a formatted citation
Spandidos Publications style
Hou Y, Yang X, Qiu D, Liu L, Shi J and Guo Y: <p>Mitochondria‑driven ferroptosis in intervertebral disc degeneration: A novel target in age‑related spinal diseases (Review)</p>. Exp Ther Med 31: 88, 2026.
APA
Hou, Y., Yang, X., Qiu, D., Liu, L., Shi, J., & Guo, Y. (2026). <p>Mitochondria‑driven ferroptosis in intervertebral disc degeneration: A novel target in age‑related spinal diseases (Review)</p>. Experimental and Therapeutic Medicine, 31, 88. https://doi.org/10.3892/etm.2026.13083
MLA
Hou, Y., Yang, X., Qiu, D., Liu, L., Shi, J., Guo, Y."<p>Mitochondria‑driven ferroptosis in intervertebral disc degeneration: A novel target in age‑related spinal diseases (Review)</p>". Experimental and Therapeutic Medicine 31.4 (2026): 88.
Chicago
Hou, Y., Yang, X., Qiu, D., Liu, L., Shi, J., Guo, Y."<p>Mitochondria‑driven ferroptosis in intervertebral disc degeneration: A novel target in age‑related spinal diseases (Review)</p>". Experimental and Therapeutic Medicine 31, no. 4 (2026): 88. https://doi.org/10.3892/etm.2026.13083
Copy and paste a formatted citation
x
Spandidos Publications style
Hou Y, Yang X, Qiu D, Liu L, Shi J and Guo Y: <p>Mitochondria‑driven ferroptosis in intervertebral disc degeneration: A novel target in age‑related spinal diseases (Review)</p>. Exp Ther Med 31: 88, 2026.
APA
Hou, Y., Yang, X., Qiu, D., Liu, L., Shi, J., & Guo, Y. (2026). <p>Mitochondria‑driven ferroptosis in intervertebral disc degeneration: A novel target in age‑related spinal diseases (Review)</p>. Experimental and Therapeutic Medicine, 31, 88. https://doi.org/10.3892/etm.2026.13083
MLA
Hou, Y., Yang, X., Qiu, D., Liu, L., Shi, J., Guo, Y."<p>Mitochondria‑driven ferroptosis in intervertebral disc degeneration: A novel target in age‑related spinal diseases (Review)</p>". Experimental and Therapeutic Medicine 31.4 (2026): 88.
Chicago
Hou, Y., Yang, X., Qiu, D., Liu, L., Shi, J., Guo, Y."<p>Mitochondria‑driven ferroptosis in intervertebral disc degeneration: A novel target in age‑related spinal diseases (Review)</p>". Experimental and Therapeutic Medicine 31, no. 4 (2026): 88. https://doi.org/10.3892/etm.2026.13083
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