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Review Open Access

Epigenetic crossroads in intervertebral disc degeneration: Unlocking novel therapeutic avenues (Review)

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

    Affiliations: Department of Orthopaedic Surgery, Changzheng Hospital, Second Military Medical University, 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: 113
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    Published online on: February 11, 2026
       https://doi.org/10.3892/mmr.2026.13823
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Abstract

Intervertebral disc degeneration (IDD) is a major pathological basis for spinal degenerative diseases, involving mechanisms such as abnormal mechanical loading, inflammatory responses, and genetic and environmental factors. The role of epigenetic regulation in IDD has gained attention as a potential therapeutic target. The present review systematically explores the contributions of DNA methylation, histone modifications, non‑coding RNAs (ncRNAs) and metabolic regulation to IDD progression, and elucidates their molecular mechanisms. Specific examples include: DNA methyltransferase 3β‑mediated DNA methylation promoting ferroptosis and oxidative stress in nucleus pulposus cells; enhancer of zeste homolog 2 (EZH2)‑mediated trimethylation of histone H3 lysine 27 modification inhibiting SOX9 expression, leading to cellular senescence and extracellular matrix degradation; and ncRNAs (such as microRNA‑143 and LINC01121) regulating gene transcription to affect inflammation and apoptosis. Additionally, metabolic products (such as NAD+, α‑ketoglutarate and lactate) interact with epigenetic pathways to influence IDD. Specifically, NAD+ acts as a cofactor for sirtuin deacetylases, thereby regulating histone and non‑histone protein acetylation; α‑ketoglutarate serves as a cofactor for TET DNA demethylases and Jumonji‑C histone demethylases, influencing DNA and histone demethylation; and lactate induces histone lactylation, which modulates gene transcription related to inflammation and extracellular matrix metabolism in IDD. Based on these mechanisms, novel therapies targeting epigenetics (such as DNA methylation inhibitors, EZH2 inhibitors and RNA interference) show therapeutic potential. Future research should further explore the crosstalk between epigenetic and metabolic regulation to advance the development of personalized and precision medicine strategies for IDD intervention.
View Figures

Figure 1

Critical role of DNA methylation
regulation in IDD. DNA methyltransferases (DNMT1, DNMT3A and
DNMT3B) mediate promoter methylation and repress target genes,
whereas TET enzymes promote demethylation and transcriptional
activation. Demethylation of SLC40A1 and GDF5 restores their
expression, thereby regulating ferroptosis resistance and ECM
homeostasis. Demethylation-mediated upregulation of DKK1, a Wnt
antagonist, inhibits Wnt signaling activity. By contrast,
hypermethylation of COL2A1, SOX9 and SPARC represses their
expression, leading to ECM degradation and accelerating IDD
progression. COL2A1, type II collagen; DKK1, dickkopf Wnt signaling
pathway inhibitor 1; DNMT, DNA methyltransferase; ECM,
extracellular matrix; GDF5, growth differentiation factor 5; IDD,
intervertebral disc degeneration; SLC40A1, solute carrier family 40
member 1; SPARC, secreted protein acidic and cysteine rich; TET,
ten-eleven translocation.

Figure 2

Role of histone modifications in IDD.
Histone acetylation and methylation influence IDD pathogenesis.
HDAC4 promotes NP cell apoptosis, whereas HDAC9 exerts protective
effects. EZH2-mediated H3K27me3 suppresses SOX9 expression,
enhancing NLRP3 inflammasome activation and extracellular matrix
degradation. By contrast, KDM2/7 promotes notochordal
differentiation, suggesting a potential therapeutic approach for
IDD. DKK1, dickkopf Wnt signaling pathway inhibitor 1; EZH2,
enhancer of zeste homolog 2; H3K27me3, trimethylation of histone H3
lysine 27; HDAC, histone deacetylase; IDD, intervertebral disc
degeneration; KDM2/7, lysine demethylase 2/7; NLRP3, NLR family
pyrin domain containing 3; NP, nucleus pulposus; Me, methyl
group.

Figure 3

Role of Non-Coding RNAs in IDD.
miRNAs repress target mRNAs, thereby regulating apoptosis,
inflammation and ECM metabolism in IDD. lncRNAs and circRNAs act as
competing endogenous RNAs that modulate miRNA activity, further
influencing IDD pathogenesis. circRNA, circular RNA; ECM,
extracellular matrix; IDD, intervertebral disc degeneration;
lncRNA, long non-coding RNA; miRNA, microRNA.

Figure 4

Interaction between metabolic
regulation and epigenetics in IDD. ROS, NAD+, lactate
and α-ketoglutarate regulate histone and DNA modifications, thereby
affecting cellular senescence, ECM homeostasis and inflammation.
These metabolism-epigenetics interactions drive the initiation and
progression of IDD. ECM, extracellular matrix; H3K4, histone H3
lysine 4; IDD, intervertebral disc degeneration; KMT2D, lysine
methyltransferase 2D; ROS, reactive oxygen species; SIRT, sirtuin;
TET, ten-eleven translocation.
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Copy and paste a formatted citation
Spandidos Publications style
Hou Y, Liu L, Guo Y and Shi J: Epigenetic crossroads in intervertebral disc degeneration: Unlocking novel therapeutic avenues (Review). Mol Med Rep 33: 113, 2026.
APA
Hou, Y., Liu, L., Guo, Y., & Shi, J. (2026). Epigenetic crossroads in intervertebral disc degeneration: Unlocking novel therapeutic avenues (Review). Molecular Medicine Reports, 33, 113. https://doi.org/10.3892/mmr.2026.13823
MLA
Hou, Y., Liu, L., Guo, Y., Shi, J."Epigenetic crossroads in intervertebral disc degeneration: Unlocking novel therapeutic avenues (Review)". Molecular Medicine Reports 33.4 (2026): 113.
Chicago
Hou, Y., Liu, L., Guo, Y., Shi, J."Epigenetic crossroads in intervertebral disc degeneration: Unlocking novel therapeutic avenues (Review)". Molecular Medicine Reports 33, no. 4 (2026): 113. https://doi.org/10.3892/mmr.2026.13823
Copy and paste a formatted citation
x
Spandidos Publications style
Hou Y, Liu L, Guo Y and Shi J: Epigenetic crossroads in intervertebral disc degeneration: Unlocking novel therapeutic avenues (Review). Mol Med Rep 33: 113, 2026.
APA
Hou, Y., Liu, L., Guo, Y., & Shi, J. (2026). Epigenetic crossroads in intervertebral disc degeneration: Unlocking novel therapeutic avenues (Review). Molecular Medicine Reports, 33, 113. https://doi.org/10.3892/mmr.2026.13823
MLA
Hou, Y., Liu, L., Guo, Y., Shi, J."Epigenetic crossroads in intervertebral disc degeneration: Unlocking novel therapeutic avenues (Review)". Molecular Medicine Reports 33.4 (2026): 113.
Chicago
Hou, Y., Liu, L., Guo, Y., Shi, J."Epigenetic crossroads in intervertebral disc degeneration: Unlocking novel therapeutic avenues (Review)". Molecular Medicine Reports 33, no. 4 (2026): 113. https://doi.org/10.3892/mmr.2026.13823
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