Analysis of the role of PANoptosis in intervertebral disk degeneration via integrated bioinformatics analysis and experimental validation.

Abstract

Intervertebral disc degeneration (IVDD) is an age-related orthopedic degenerative disease characterized by recurrent episodes of lower back pain, and death of nucleus pulposus cells (NPCs) has been identified as a key factor in the pathophysiological process of IVDD episodes. Recent studies have shown that " PANapoptosis ", a newly characterized form of cell death, has emerged as an important factor contributing to the development of several diseases. However, studies on the specific mechanisms of its role in the development of IVDD are lacking. The aim of this study was to explore the characterization of PANoptosis in IVDD and to identify potential biomarkers and therapeutic targets as well as therapeutic agents. We constructed a PANoptosis gene set, based on the GEO database, and used weighted gene co-expression network analysis (WGCNA) and differential expression analysis to identify PANoptosis genes associated with the pathophysiological process of IVDD episodes by Gene Set Enrichment Analysis (GSEA), immune infiltration, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to explore the underlying biological mechanisms of PANoptosis and its role in IVDD. Comprehensive bioinformatics analysis showed that seven key genes (APAF1, MEFV, NLRP3, TNF, GSDMD, AIM2, and IRF1) of PANoptosis have good diagnostic value. In addition, we predicted potential therapeutic agents, among which Andrographolide (AG) had the highest correlation and binding affinity to the target. Finally, we performed Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) assays, molecular docking, and cell flow to validate the expression of PANoptosis-related genes and the therapeutic effect of AG. We further divided SD rats into sham-operated, IVDD model, and Andrographolide-treated groups, administered AG at 50 mg/kg via gavage for one month, and observed significant therapeutic effects through HE staining. This study identifies key PANoptosis genes and demonstrates the potential of AG as a therapeutic agent for IVDD.