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Background <p>Intervertebral disc (IVD) degeneration (IDD) represents a predominant origin of low back pain and disability, yet current therapeutic interventions remain suboptimal. Emerging evidence highlights autophagy activation as a therapeutic strategy against IDD. This study investigates the mechanistic interplay between N6-methyladenosine (m6A) modifications and autophagy dysregulation in IDD pathogenesis.</p> Methods <p>Bioinformatics analysis identified ring finger protein 41 (<i>RNF41</i>) as a key autophagy-IDD intersection gene. Functional validation utilized tert-butyl hydroperoxide (TBHP)-treated human nucleus pulposus (NP) cells to assess RNF41’s effects on senescence (CDKN2A), autophagy (LC3-II/p62), apoptosis (TUNEL), inflammation (IL-18/IL-1β), and extracellular matrix (ECM) homeostasis (aggrecan/MMP). Key m6A regulators modulating autophagy were screened via correlation analysis. <i>In vivo</i> validation employed adeno-associated virus (AAV)-mediated methyltransferase-like 3 (METTL3)/RNF41 delivery in puncture-induced IDD rat models.</p> Results <p>RNF41 expression was downregulated in human IVD tissues. Overexpression of RNF41 mitigated TBHP-induced senescence, apoptosis, activated AMPK/mTOR-mediated autophagy, suppressed inflammation, and restored ECM balance. The autophagy inhibitor chloroquine (CQ) abolished the protective effects of RNF41 overexpression on degenerative NP cells. Mechanistically, METTL3/YTHDC1 co-regulation in degenerative NP cells mediated m6A hypermethylation of <i>RNF41</i> mRNA, shortening its half-life via YTHDC1-dependent decay. Intradiscal METTL3-silencing AAV attenuated puncture-induced disc loss and histopathological degeneration, whereas RNF41-silencing AVV exacerbated ECM disruption and annular disorganization.</p> Conclusion <p>METTL3/YTHDC1-mediated m6A modification drives IDD progression by silencing <i>RNF41</i>, thereby impairing autophagy and ECM integrity. Targeting this axis offers a clinically actionable strategy to delay disc degeneration, particularly in patients with early-stage IDD. This evidence establishes RNF41’s role as a theragnostic biomarker and therapeutic targe, enabling precision-guided interventional approaches.</p>

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m6A-mediated silencing of RNF41 by METTL3/YTHDC1 disrupts autophagy to drive intervertebral disc degeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月3日

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  • Bo Yao,
  • Li Wan,
  • Jia Deng,
  • Zhengyu Chen,
  • Lei Zhao,
  • Weiguo Wang,
  • Ziwei Han

摘要

Background

Intervertebral disc (IVD) degeneration (IDD) represents a predominant origin of low back pain and disability, yet current therapeutic interventions remain suboptimal. Emerging evidence highlights autophagy activation as a therapeutic strategy against IDD. This study investigates the mechanistic interplay between N6-methyladenosine (m6A) modifications and autophagy dysregulation in IDD pathogenesis.

Methods

Bioinformatics analysis identified ring finger protein 41 (RNF41) as a key autophagy-IDD intersection gene. Functional validation utilized tert-butyl hydroperoxide (TBHP)-treated human nucleus pulposus (NP) cells to assess RNF41’s effects on senescence (CDKN2A), autophagy (LC3-II/p62), apoptosis (TUNEL), inflammation (IL-18/IL-1β), and extracellular matrix (ECM) homeostasis (aggrecan/MMP). Key m6A regulators modulating autophagy were screened via correlation analysis. In vivo validation employed adeno-associated virus (AAV)-mediated methyltransferase-like 3 (METTL3)/RNF41 delivery in puncture-induced IDD rat models.

Results

RNF41 expression was downregulated in human IVD tissues. Overexpression of RNF41 mitigated TBHP-induced senescence, apoptosis, activated AMPK/mTOR-mediated autophagy, suppressed inflammation, and restored ECM balance. The autophagy inhibitor chloroquine (CQ) abolished the protective effects of RNF41 overexpression on degenerative NP cells. Mechanistically, METTL3/YTHDC1 co-regulation in degenerative NP cells mediated m6A hypermethylation of RNF41 mRNA, shortening its half-life via YTHDC1-dependent decay. Intradiscal METTL3-silencing AAV attenuated puncture-induced disc loss and histopathological degeneration, whereas RNF41-silencing AVV exacerbated ECM disruption and annular disorganization.

Conclusion

METTL3/YTHDC1-mediated m6A modification drives IDD progression by silencing RNF41, thereby impairing autophagy and ECM integrity. Targeting this axis offers a clinically actionable strategy to delay disc degeneration, particularly in patients with early-stage IDD. This evidence establishes RNF41’s role as a theragnostic biomarker and therapeutic targe, enabling precision-guided interventional approaches.