SOX4 accelerates intervertebral disc degeneration via EZH2/NRF2 pathway in response to mitochondrial ROS-dependent NLRP3 inflammasome activation in nucleus pulposus cells.

Objective: The transcription factor SRY-related HMG-box 4 (SOX4) has been implicated in intervertebral disc diseases. This study aimed to investigate the role of SOX4 in intervertebral disc degeneration (IDD) and explore the underlying molecular mechanisms.

Methods: We established an IDD rat model via surgery and analyzed SOX4 expression using qRT-PCR and Western blotting. Histological evaluation, immunohistochemistry, and Safranin O staining assessed IDD progression. In vitro, an IDD cellular model was constructed using IL-1β-stimulated nucleus pulposus (NP) cells. SOX4 knockdown and overexpression experiments in NP cells examined SOX4 effects on ECM degradation, NLRP3-mediated pyroptosis, and mitochondrial ROS-dependent NLRP3 inflammasome activation. The involvement of the EZH2/NRF2 pathway in SOX4-mediated NLRP3 activation was also examined.

Results: SOX4 expression was significantly increased in IDD rats and promoted IDD progression. Knockdown of SOX4 inhibited ECM degradation and NLRP3-mediated pyroptosis in NP cells. In vitro experiments showed that SOX4 promoted ECM degradation by upregulating MMPs and ADAMTS-5 expression, and suppressed collagen II and aggrecan synthesis. SOX4 knockdown inhibited NLRP3-mediated pyroptosis, while overexpression accelerated it in NP cells. Additionally, SOX4 was found to exacerbate mitochondrial ROS-dependent NLRP3 inflammasome activation in NP cells. Further investigation revealed that SOX4 enhanced NLRP3 inflammasome activation by upregulating EZH2 expression and modulating the EZH2/NRF2 pathway, with EZH2 inhibition attenuating SOX4-induced NLRP3 activation.

Conclusions: Our findings suggest that SOX4 accelerates IDD progression by promoting NLRP3 inflammasome activation via modulating the EZH2/NRF2 pathway, leading to NP cell pyroptosis and ECM degradation. Targeting SOX4 may represent a potential therapeutic strategy for treating IDD.