A Novel Pyroptosis-related Gene Signature for Predicting Prognosis and Immune Infiltration in Osteosarcoma

Abstract

Background: Osteosarcoma is the most prevalent primary malignant bone malignancy with a dismal prognosis in children and adolescents. Pyroptosis, a proinflammatory form of programmed cell death, plays a pivotal role in oncogenesis and tumor progression across various malignancies. However, the prognostic relevance of pyroptosis-related genes (PRGs) in osteosarcoma remains poorly understood. In this study, we aimed to establish and validate a novel PRG-based prognostic signature to enhance survival prediction for osteosarcoma patients. Methods: Transcriptomic data and corresponding clinical profiles of osteosarcoma were retrieved from the UCSC Xena database. PRGs were identified from established literature, and bioinformatics analyses were performed to isolate differentially expressed genes (DEGs). Non-negative matrix factorization (NMF) clustering was applied to identify molecular subgroups based on PRG expression patterns. LASSO-Cox regression analysis was utilized to construct the novel model. Subsequently, we constructed a nomogram and calibration curves incorporating the risk score and clinical characteristics. Finally, Gene Set Enrichment Analysis (GSEA) and immune microenvironment characterization were performed to investigate the functional pathways and immunological landscapes associated with the signature. Results: A novel prognostic signature comprising four key PRGs was established. Kaplan–Meier survival analysis demonstrated that patients in the high-risk group had a significantly poorer overall survival. Independent Cox analysis illustrated that this risk model serves as an independent prognostic indicator. In addition, we validated the accuracy of our signature in the validation dataset. Furthermore, the nomogram and calibration curves confirmed the robust prediction efficiency of the novel model. Notably, GSEA and immune microenvironment analysis showed that the low-risk group was significantly enriched in immune-related pathways and possessed a superior immune status, indicating that the divergent clinical outcomes between the two risk groups mainly result from the regulation of the immune microenvironment. Conclusion: The identified four-gene pyroptosis-related signature is a promising prognostic biomarker for osteosarcoma. These findings provide novel insights that may improve survival outcomes and guide personalized therapeutic strategies for osteosarcoma patients.