TIGAR attenuates intervertebral disc degeneration via autophagy-mediated Keap1 degradation and Nrf2 nuclear translocation to suppress nucleus pulposus pyroptosis.

Pyroptosis plays a pivotal role in intervertebral disc degeneration (IVDD) driven by oxidative-inflammatory cascades, inducing nucleus pulposus (NP) cell lysis through gasdermin-mediated pore formation and subsequent release of proinflammatory cytokines, including IL-1β and IL-18. TP53-induced glycolysis and apoptosis regulator (TIGAR) alleviates oxidative stress by scavenging reactive oxygen species (ROS); however, its involvement in the autophagy-pyroptosis axis mediating IVDD remains unclear. In this study, we aimed to investigate how TIGAR delays IVDD progression via the autophagy-pyroptosis axis. First, we discovered from the NP tissues collected from patients undergoing lumbar spine surgeries and mice with needle puncture-induced models that the expression of TIGAR was reduced in severely degenerated tissues. In the IL-1β-induced human NP cell, TIGAR knockdown exacerbated the degradation of the extracellular matrix and pyroptosis, whereas TIGAR overexpression reversed this phenomenon. Ultrastructural analysis via transmission electron microscopy (TEM) and autophagic flux quantification revealed TIGAR-mediated autophagy in NP cells under inflammatory conditions. Co-immunoprecipitation assays validated the formation of a Keap1-p62-ubiquitin ternary complex, which directed Keap1 toward lysosome-dependent degradation and enhanced Nrf2 nuclear translocation. Therapeutic intradiscal delivery of AAV-TIGAR attenuated IVDD progression in mouse models, evidenced by preserved disc height index and reduced histopathological scores. Collectively, this work identified TIGAR as a redox-sensitive molecular switch that mitigated oxidative stress and inflammasome-driven pyroptosis through Keap1 autophagic clearance, offering a novel therapeutic paradigm for precision-targeted IVDD intervention.