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Abstract Osteoarthritis (OA), a degenerative disease of the joints, has one of the highest disability rates worldwide. This study investigates the role of pyroptosis-related genes in osteoarthritis and their expression in different chondrocyte subtypes at the individual cell level. Using OA-related datasets for single-cell RNA sequencing and RNA-seq, the study identified PRDEGs and DEGs and conducted Cox regression analysis to identify independent prognostic factors for OA. CASP6, NOD1, and PYCARD were found to be prognostic factors. Combined Weighted Gene Correlation Network Analysis with PPI network, a total of 15 hub genes related to pyroptosis were involved in the notch and oxidative phosphorylation pathways, which could serve as biomarkers for the diagnosis and prognosis of OA patients. The study also explored the heterogeneity of chondrocytes between OA and normal samples, identifying 19 single-cell subpopulation marker genes that were significantly different among 7 chondrocyte cell clusters. AGT, CTSD, CYBC, and THYS1 were expressed differentially among different cell subpopulations, which were associated with cartilage development and metabolism. These findings provide valuable insights into the molecular mechanisms underlying OA and could facilitate the development of new therapeutic strategies for this debilitating disease.