Background <p>Intervertebral disc degeneration (IVDD) acts as the prerequisite and pathological basis for a series of spinal degenerative diseases, and it remains one of the most harmful and difficult-to-treat conditions in this category. However, the exact pathogenesis of IVDD has not been fully elucidated.</p> Methods <p>Comprehensive analysis of data mining, bioinformatics and real-time quantitative PCR was used to pinpoint the key transcription factors participated in the progression of IVDD. The role of early growth response factor 1 (EGR1) in IVDD was determined through a series of loss- and gain-of-function experiments in vitro and in vivo. Mechanistically, bioinformatics, chromatin immunoprecipitation, and dual-luciferase reporter assays were applied to illustrate the interaction mechanism between microRNA-4306 (miR-4306) and Methionine adenosyltransferase 2A (MAT2A), or EGR1. Finally, rescue experiments were designed to&#xa0;assess the impact of the EGR1/miR-4306/MAT2A axis on nucleus pulposus cell function in vitro.</p> Results <p>EGR1 was highly expressed in degenerated nucleus pulposus tissues and lipopolysaccharide-induced nucleus pulposus cells, and expression levels of EGR1 were positively relevant with IVDD pathological grade. EGR1 overexpression aggravated lipopolysaccharide-induced pyroptosis and extracellular matrix degradation of nucleus pulposus cells, while EGR1 knockdown inhibited these effects in vitro and alleviated IVDD progression in mice in vivo. Mechanistically, EGR1 directly suppressed miR-4306 transcription by binding its promoter, and MAT2A was a target gene of miR-4306. Rescue experiments confirmed EGR1 knockdown inhibited lipopolysaccharide-induced nucleus pulposus cells damage by mediating the miR-4306/MAT2A axis.</p> Conclusion <p>This study suggested the EGR1/miR-4306/MAT2A axis played an important role in IVDD pathogenesis, which might be promising therapeutic targets for IVDD.</p>