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SOX4 accelerates intervertebral disc degeneration via EZH2/NRF2 pathway in response to mitochondrial ROS-dependent

Wenzhi Zhao1, Yadong Liu2, Yunxiang Hu2

  • 1Department of Traumatic Orthopedics, The Second Affiliated Hospital, Dalian Medical University, Dalian, 116011, China.

Journal of Translational Medicine
|April 4, 2025
PubMed
Abstract

Insights

SRY-related HMG-box 4 (SOX4) drives intervertebral disc degeneration (IDD) by activating NLRP3 inflammasomes, causing cell death and matrix breakdown. Targeting SOX4 offers a potential therapeutic approach for IDD.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Intervertebral disc degeneration (IDD) is a significant cause of back pain.
  • The transcription factor SOX4 (SRY-related HMG-box 4) has been linked to IDD.
  • Understanding SOX4's role is crucial for developing new IDD therapies.

Purpose of the Study:

  • To investigate the role of SOX4 in intervertebral disc degeneration (IDD).
  • To explore the molecular mechanisms by which SOX4 influences IDD.
  • To assess SOX4's impact on extracellular matrix (ECM) degradation and nucleus pulposus (NP) cell pyroptosis.

Main Methods:

  • An IDD rat model was established and SOX4 expression analyzed.
  • In vitro NP cell models were used to study SOX4's effects on ECM, pyroptosis, and inflammasome activation.
  • Experiments included SOX4 knockdown/overexpression, qRT-PCR, Western blotting, and histological analysis.
  • The involvement of the EZH2/NRF2 pathway in SOX4-mediated NLRP3 activation was examined.

Main Results:

  • SOX4 expression was elevated in IDD models and correlated with disease progression.
  • SOX4 knockdown reduced ECM degradation and NLRP3-mediated pyroptosis in NP cells.
  • SOX4 promoted ECM degradation by upregulating MMPs and ADAMTS-5, while suppressing collagen II and aggrecan synthesis.
  • SOX4 exacerbated mitochondrial ROS-dependent NLRP3 inflammasome activation, partly via the EZH2/NRF2 pathway.

Conclusions:

  • SOX4 accelerates IDD by promoting NLRP3 inflammasome activation, leading to NP cell pyroptosis and ECM degradation.
  • The EZH2/NRF2 pathway is implicated in SOX4's modulation of NLRP3 activation.
  • Targeting SOX4 presents a promising therapeutic strategy for IDD treatment.
Keywords:
EZH2/NRF2 pathwayExtracellular matrix degradationIntervertebral disc degenerationNLRP3 inflammasome activationPyroptosisSRY-related HMG-box 4

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