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<p>Intervertebral disc degeneration (IVDD) is a major contributor to low back pain, yet its cellular and molecular mechanisms remain incompletely understood. In this study, we integrated single-cell and bulk transcriptomic data to uncover the role of senescence-associated secretory phenotype (SASP) signaling in IVDD progression. Single-cell RNA sequencing delineated the heterogeneity of nucleus pulposus cells (NPCs) subtypes and revealed significant differences in senescence levels and SASP activity. Bulk RNA-seq integration across multiple datasets further confirmed widespread SASP activation and defined a core regulatory network centered on Bone Morphogenetic Protein 2 (BMP2) and Matrix Metalloproteinase 3 (MMP3), identified via WGCNA and machine learning algorithms (LASSO, Random Forest, Boruta). A SASP scoring model based on these two genes showed strong diagnostic performance. Drug screening identified Simvastatin as a high-affinity dual inhibitor of BMP2/MMP3, with molecular docking supporting its therapeutic potential. In vitro, Simvastatin treatment reduced NPCs senescence and apoptosis, while in vivo studies demonstrated that Simvastatin preserved disc structure, decreased pro-inflammatory cytokine levels, and mitigated degenerative changes in a murine IVDD model. Collectively, this study establishes a regulatory framework of SASP in IVDD and proposes BMP2/MMP3 as promising targets for intervention. Our findings offer insights and a potential translational path for slowing disc degeneration.</p> Graphical Abstract <p></p>

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Machine Learning Identifies Key Cells and Therapeutic Targets in Intervertebral Disc Degeneration: SASP-Driven Matrix Catabolism, Inflammation Amplification, and Metabolic Collapse

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月7日

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  • Yi Kang,
  • Manglai Li,
  • Baoyang Hu,
  • Yigang Lv,
  • Jiawei Du,
  • Di Zhang,
  • Hengxing Zhou,
  • Shiqing Feng

摘要

Intervertebral disc degeneration (IVDD) is a major contributor to low back pain, yet its cellular and molecular mechanisms remain incompletely understood. In this study, we integrated single-cell and bulk transcriptomic data to uncover the role of senescence-associated secretory phenotype (SASP) signaling in IVDD progression. Single-cell RNA sequencing delineated the heterogeneity of nucleus pulposus cells (NPCs) subtypes and revealed significant differences in senescence levels and SASP activity. Bulk RNA-seq integration across multiple datasets further confirmed widespread SASP activation and defined a core regulatory network centered on Bone Morphogenetic Protein 2 (BMP2) and Matrix Metalloproteinase 3 (MMP3), identified via WGCNA and machine learning algorithms (LASSO, Random Forest, Boruta). A SASP scoring model based on these two genes showed strong diagnostic performance. Drug screening identified Simvastatin as a high-affinity dual inhibitor of BMP2/MMP3, with molecular docking supporting its therapeutic potential. In vitro, Simvastatin treatment reduced NPCs senescence and apoptosis, while in vivo studies demonstrated that Simvastatin preserved disc structure, decreased pro-inflammatory cytokine levels, and mitigated degenerative changes in a murine IVDD model. Collectively, this study establishes a regulatory framework of SASP in IVDD and proposes BMP2/MMP3 as promising targets for intervention. Our findings offer insights and a potential translational path for slowing disc degeneration.

Graphical Abstract