Necroptosis is a critical process in intervertebral disc degeneration (IDD). This research is aimed at identifying key genes regulating necroptosis in IDD to provide a theoretical basis for early diagnosis and treatment. Transcriptome data from patients with IDD and normal samples were obtained from the GSE34095 and GSE124272 datasets of the Gene Expression Omnibus (GEO) public database. Necroptosis-related genes (NRGs) were sourced from the GeneCards database and literature. Differentially expressed necroptosis-related genes (DE-NRGs) in IDD were identified by intersecting these sources. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for gene annotation analysis. The receiver operating characteristic (ROC) curve and nomogram analyses assessed the diagnostic efficiency of DE-NRGs. The miRWalk and starBase databases helped construct the competing endogenous RNA (ceRNA) regulatory network of DE-NRGs. We identified 517 differential genes in tissue and 2974 in blood, with 62 genes in common. DE-NRGs (AIFM1, CCT8, HNRNPA1, KHDRBS1, SERBP1) were identified by intersecting NRGs with these 62 common genes. The ROC curve showed an area under the curve (AUC) > 0.70 for DE-NRGs, and the nomogram indicated that a higher DE-NRG score correlates with a higher risk of IDD. CCT8, KHDRBS1, and AIFM1 emerged as potential therapeutic targets for IDD through target drug prediction. qRT-PCR (quantitative reverse transcription polymerase chain reaction), Western blot, and immunohistochemistry confirmed the expression of AIFM1, CCT8, HNRNPA1, KHDRBS1, and SERBP1 in patients' nucleus pulposus tissue, suggesting these genes as key targets for IDD risk assessment and drug therapy.Copyright © 2024 Fan Zhang et al.