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Epigenetic crossroads in intervertebral disc degeneration: Unlocking novel therapeutic avenues (Review)
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DOI：10.3892/mmr.2026.13823.png)
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Abstract
En 中文
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 3 beta-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+, alpha-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; alpha-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.
Keywords:
intervertebral disc degeneration
epigenetics
DNA methylation
histone modifications
non-coding RNA
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