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August 30, 2026Advanced ScienceOpen Access

ACSL4‐Dependent Lysosomal Lipid Peroxidation Links WTAP‐Mediated m 6 A Modification to Intervertebral Disc Degeneration

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Authors

SJShu JiaAffiliated Hospital of Jining Medical UniversityXGXu GaoLZLaimin ZhuAffiliated Hospital of Jining Medical University

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Implication

Translational study reveals that WTAP-driven lipid peroxidation promotes disc degeneration in cellular and rat models, highlighting a potential therapeutic target for back pain.

Key Points

  • Identify the epigenetic and molecular mechanisms by which m6A RNA modification regulates lysosomal membrane permeabilization and drives intervertebral disc degeneration.
  • Analyzed human nucleus pulposus tissues using single-cell transcriptomics to evaluate lysosomal gene pathways, membrane permeabilization, and mitophagy flux across stages of degeneration.
  • Treated cultured nucleus pulposus cells with interleukin-1β to evaluate the downstream WTAP, IGF2BP2, and ACSL4 signaling cascades and lipid peroxidation.
  • Delivered AAV9-shWTAP via intradiscal injection to assess therapeutic preservation of disc height and extracellular matrix in a rat model of disc degeneration.
  • Interleukin-1β upregulated the m6A methyltransferase component WTAP to methylate ACSL4 mRNA, which the reader IGF2BP2 stabilized to promote arachidonic acid-containing phospholipid accumulation and lysosomal membrane permeabilization.
  • Intradiscal silencing of WTAP via AAV9 in rats attenuated disc degeneration, preserved disc height, improved extracellular matrix synthesis, and restored lysosomal function and mitophagy flux.

Cite This Study

Jia et al. (2026) studied this question.

synapsesocial.com/papers/6a93f1736c1a8fb52e79e5dfhttps://doi.org/10.1002/advs.77401
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Also Consider

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  1. 1Abnormal stress promotes intervertebral disc degeneration through WTAP/YTHDF2‐dependent TIMP3 m6A modification2024 · 11 citations
  2. 2Dysregulated methylation-ubiquitination crosstalk accelerates intervertebral disc degeneration via MED12 destabilization and cGAS/STING activation2026 · 1 citations
  3. 3Methylmalonic Acid, an Aging‐Associated Metabolite, Accelerates Intervertebral Disc Degeneration by Inducing Disc Vascularization via the CCL7 / JAK2 ‐ STAT3 / VEGF Signaling Axis2026 · 3 citations
  4. 4Inhibition of PLA2G15 Alleviates Palmitic Acid‐Induced Lysosomal Membrane Permeabilization in Human Nucleus Pulposus Cells During Intervertebral Disc Degeneration2026
  5. 5Inhibition of lactylation by LRP1 expression increases the risk of intervertebral disc degeneration: A multi-omics summary-based Mendelian randomization analysis2025 · 4 citations