Gliomas are highly invasive and aggressive tumors having the highest incidence rate of brain cancer. Identifying effective prognostic and potential therapeutic targets is necessitated. The relationship of pyroptosis, a form of programmed cellular death, with gliomas remains elusive. We constructed and validated a prognostic model for gliomas using pyroptosis-related genes. Differentially expressed pyroptosis-related genes were screened using the "limma" package. Based on LASSO-Cox regression, nine significant genes including CASP1, CASP3, CASP6, IL32, MKI67, MYD88, PRTN3, NOS1, and VIM were employed to construct a prognostic model in the TCGA cohort; the results were validated in the CGGA cohort. According to the median risk score, the patients were classified into two risk groups, namely, high- and low-risk groups. Patients at high risk had worse prognoses relative to those at low risk evidenced by the Kaplan-Meier curve analysis. The two groups exhibited differences in immune cell infiltration and TMB scores, with high immune checkpoint levels, TMB scores, and immune cell infiltration levels in the high-risk group. KEGG and GO analyses suggested enrichment in immune-related pathways. Furthermore, we found that the genes in our signature strongly correlated with oxidative stress-related pathways and the subgroups exhibited different ssGSEA scores. Some small molecules targeted the genes in the model, and we verified their drug sensitivities between the risk groups. The scRNA-seq dataset, GSE138794, was processed using the "Seurat" package to assess the level of risk gene expression in specific cell types. Finally, the MYD88 level was lowered in the U87 glioma cell line using si-RNA constructs. Cellular proliferation was impaired, and fewer pyroptosis-related cytokines were released upon exposure to LPS. In summary, we built a pyroptosis-related gene model that accurately classified glioma patients into high- and low-risk groups. The findings suggest that the signature may be an effective prognostic predictive tool for gliomas.Copyright © 2023 Shulian Zeng et al.