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<p>Intervertebral disc degeneration (IDD) is closely linked to nucleus pulposus (NP) cell death exhibiting a PANoptotic phenotype—concurrent activation of apoptosis, necroptosis, and pyroptosis—yet its molecular regulators remain unclear. Here we identify DNA damage-inducible transcript 3 (DDIT3) as a key mediator of inflammatory PANoptosis. RNA sequencing of TNF-α–treated human NP cells revealed robust DDIT3 upregulation, consistent with observations in degenerated human discs and a rat needle-puncture IDD model. In vitro, DDIT3 knockdown (siRNA) reduced PANoptosis markers (NLRP3, caspase-1 p20, Bax, cleaved caspase-3, MLKL, p-MLKL), inflammatory cytokines (IL-1β, IL-18), and reactive oxygen species (ROS), whereas DDIT3 overexpression produced the opposite effects. Mechanistically, transcriptomics and luciferase assays indicated that DDIT3 transactivates CUL3; direct promoter binding was corroborated by chromatin immunoprecipitation and electrophoretic mobility shift assays. Molecular docking (predictive) together with co-immunoprecipitation supported a CUL3–caspase-8 interaction, and CUL3-dependent polyubiquitination enhanced caspase-8 activation. In vivo, lentiviral DDIT3 silencing mitigated disc degeneration in rat puncture models, preserved aggrecan/collagen II, and reduced PANoptotic readouts, whereas DDIT3 overexpression accelerated matrix loss. Collectively, these findings position the DDIT3–CUL3–caspase-8 axis as a central regulator of inflammatory PANoptosis in NP cells and a potential therapeutic target for halting IDD progression.</p>

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DDIT3 drives nucleus pulposus cell PANoptosis and intervertebral disc degeneration progression

  • 期刊论文

  • 发表日期：

    2026年1月10日

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  • Kun Wang,
  • Hangyu Ji,
  • Jiawei Gao,
  • Zhiqiang Wang,
  • Yanzheng Gao,
  • Xiaofeng Lian,
  • Xin Peng

摘要

Intervertebral disc degeneration (IDD) is closely linked to nucleus pulposus (NP) cell death exhibiting a PANoptotic phenotype—concurrent activation of apoptosis, necroptosis, and pyroptosis—yet its molecular regulators remain unclear. Here we identify DNA damage-inducible transcript 3 (DDIT3) as a key mediator of inflammatory PANoptosis. RNA sequencing of TNF-α–treated human NP cells revealed robust DDIT3 upregulation, consistent with observations in degenerated human discs and a rat needle-puncture IDD model. In vitro, DDIT3 knockdown (siRNA) reduced PANoptosis markers (NLRP3, caspase-1 p20, Bax, cleaved caspase-3, MLKL, p-MLKL), inflammatory cytokines (IL-1β, IL-18), and reactive oxygen species (ROS), whereas DDIT3 overexpression produced the opposite effects. Mechanistically, transcriptomics and luciferase assays indicated that DDIT3 transactivates CUL3; direct promoter binding was corroborated by chromatin immunoprecipitation and electrophoretic mobility shift assays. Molecular docking (predictive) together with co-immunoprecipitation supported a CUL3–caspase-8 interaction, and CUL3-dependent polyubiquitination enhanced caspase-8 activation. In vivo, lentiviral DDIT3 silencing mitigated disc degeneration in rat puncture models, preserved aggrecan/collagen II, and reduced PANoptotic readouts, whereas DDIT3 overexpression accelerated matrix loss. Collectively, these findings position the DDIT3–CUL3–caspase-8 axis as a central regulator of inflammatory PANoptosis in NP cells and a potential therapeutic target for halting IDD progression.