Background <p>Cellular senescence and the senescence-associated secretory phenotype (SASP) are increasingly recognized as contributors to intervertebral disc degeneration (IVDD). However, clinically relevant SASP-related gene signatures and therapeutic implications remain incompletely defined.</p> Methods <p>Two peripheral whole-blood transcriptomic datasets from GEO (GSE124272 and GSE150408) were integrated. SASP-associated differentially expressed genes (DEGs) were identified by intersecting DEGs between IVDD and control samples with the SenMayo gene set, a literature-derived senescence panel composed predominantly of SASP factors. Functional enrichment analysis and immune infiltration profiling were performed. Hub genes were prioritized using protein-protein interaction networks, consensus clustering, and weighted gene co-expression network analysis. Candidate compounds were predicted using the Connectivity Map and further supported by molecular docking. The candidate drug was further evaluated in vitro using IL-1β-stimulated mouse nucleus pulposus cells by RT-qPCR and Western blotting, and in vivo in a mouse needle-puncture IVDD model assessed by micro-CT and histology.</p> Results <p>A four-gene SASP-related signature (MMP9, CXCL1, TNFRSF1A, and CXCR2) was significantly associated with IVDD and linked to NF-κB signaling and cellular senescence pathways by gene set enrichment analysis. The signature correlated with pro-inflammatory innate immune infiltration, particularly neutrophils and M0 macrophages. Pinocembrin (PC) exhibited favorable predicted binding affinity to the proteins encoded by the four signature genes. PC suppressed IL-1β-induced upregulation of these signature genes at both mRNA and protein levels in vitro and preserved disc height and structural integrity in vivo.</p> Conclusion <p>This study identifies a four-gene SASP-related signature associated with IVDD and provides preclinical evidence supporting pinocembrin as a potential therapeutic candidate.</p>