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<p>Intervertebral disc degeneration (IVDD) is a major cause of chronic low back pain and disability, but its molecular mechanisms are not fully understood. Recent studies highlight the role of m6A RNA methylation in cellular senescence and extracellular matrix regulation. This study explores the role of METTL14, a key m6A “writer” in regulating LRIG1 expression and its involvement in IVDD pathogenesis. METTL14 expression was evaluated in nucleus pulposus (NP) tissues from IVDD patients at different degeneration stages using immunohistochemistry. In vitro experiments were conducted with METTL14 knockdown and TNF-α-induced cellular degeneration in NP cells. The effects on cellular senescence markers, ECM components, and m6A RNA methylation were examined. m6A RNA immunoprecipitation was employed to assess m6A modification levels. Bioinformatics tools predicted potential m6A sites on LRIG1 mRNA, which were further validated by luciferase reporter assays. METTL14 expression was significantly upregulated in NP tissues from patients with severe IVDD. METTL14 knockdown in NP cells led to reduced m6A enrichment on LRIG1 mRNA, destabilizing LRIG1 transcripts and increasing cellular senescence marker P21. TNF-α stimulation further induced METTL14 expression, exacerbated ECM degradation, and accelerated cellular senescence. Restoration of LRIG1 expression through overexpression mitigated the degenerative changes caused by METTL14 knockdown. Luciferase assays confirmed that METTL14 regulates LRIG1 mRNA stability via specific m6A sites, establishing a METTL14-LRIG1 axis in cellular senescence. This study identifies METTL14 as a critical regulator of LRIG1-mediated ECM stability and cellular senescence in IVDD pathogenesis. The METTL14-LRIG1 axis, driven by m6A modifications, provides new mechanistic insights into the inflammatory and degenerative processes underlying IVDD. Targeting METTL14 or the associated m6A pathway may offer novel therapeutic strategies for IVDD.</p>

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METTL14 regulate LRIG1 expression via m6A to affect nucleus pulposus cell senescence in intervertebral disc degeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月17日

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  • Ruihai Xiao,
  • Qunying Yang,
  • Yingqun Yin,
  • Shanshan Peng,
  • Xigao Cheng

摘要

Intervertebral disc degeneration (IVDD) is a major cause of chronic low back pain and disability, but its molecular mechanisms are not fully understood. Recent studies highlight the role of m6A RNA methylation in cellular senescence and extracellular matrix regulation. This study explores the role of METTL14, a key m6A “writer” in regulating LRIG1 expression and its involvement in IVDD pathogenesis. METTL14 expression was evaluated in nucleus pulposus (NP) tissues from IVDD patients at different degeneration stages using immunohistochemistry. In vitro experiments were conducted with METTL14 knockdown and TNF-α-induced cellular degeneration in NP cells. The effects on cellular senescence markers, ECM components, and m6A RNA methylation were examined. m6A RNA immunoprecipitation was employed to assess m6A modification levels. Bioinformatics tools predicted potential m6A sites on LRIG1 mRNA, which were further validated by luciferase reporter assays. METTL14 expression was significantly upregulated in NP tissues from patients with severe IVDD. METTL14 knockdown in NP cells led to reduced m6A enrichment on LRIG1 mRNA, destabilizing LRIG1 transcripts and increasing cellular senescence marker P21. TNF-α stimulation further induced METTL14 expression, exacerbated ECM degradation, and accelerated cellular senescence. Restoration of LRIG1 expression through overexpression mitigated the degenerative changes caused by METTL14 knockdown. Luciferase assays confirmed that METTL14 regulates LRIG1 mRNA stability via specific m6A sites, establishing a METTL14-LRIG1 axis in cellular senescence. This study identifies METTL14 as a critical regulator of LRIG1-mediated ECM stability and cellular senescence in IVDD pathogenesis. The METTL14-LRIG1 axis, driven by m6A modifications, provides new mechanistic insights into the inflammatory and degenerative processes underlying IVDD. Targeting METTL14 or the associated m6A pathway may offer novel therapeutic strategies for IVDD.