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<p>Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage destruction. Emerging evidence suggests that chondrocyte pyroptosis, a pro-inflammatory programmed cell death pathway, contributes to OA pathogenesis. However, the molecular mechanisms underlying pyroptosis in OA and potential therapeutic interventions remain incompletely understood. Bulk RNA-seq datasets (GSE114007 and GSE254844) were analyzed to identify differentially expressed genes (DEGs) and co-expression modules via DESeq2 and WGCNA. Shared key DEGs (SKDEGs) were subjected to GO and KEGG enrichment analyses to reveal relevant pathways. Pyroptosis-related DEGs (PRDEGs) were intersected with SKDEGs and used for drug prediction in EnrichR. Predicted compounds were further examined for potential targets using TCMSP, HIT, and SwissTargetPrediction databases to identify hub genes. Single-cell RNA-seq data (GSE169454) were analyzed to determine the cellular localization, differential expression, and pathway activity of hub genes. Finally, in vitro experiments with primary human normal and OA chondrocytes were performed to validate the effects of the identified compound on cell proliferation and pyroptosis. Analysis of bulk RNA-seq data identified 146 SKDEGs, with pyroptosis emerging as the most significantly enriched pathway. Six PRDEGs were identified, and curcumin was predicted as a key therapeutic compound. Intersection of curcumin targets with PRDEGs revealed four hub genes (CASP1, IL1B, IL18, NLRP3), all upregulated in OA. Single-cell analysis confirmed that these hub genes were predominantly expressed in OA-associated chondrocyte subtypes, with increased pathway activity and expression along pseudotime trajectories. In vitro, curcumin (10&#xa0;µM) promoted chondrocyte proliferation and significantly suppressed the mRNA and protein expression of the hub genes, indicating inhibition of pyroptosis. Chondrocyte pyroptosis is a critical contributor to OA progression, and curcumin can alleviate OA by targeting pyroptosis-related pathways. This integrative study provides mechanistic insights and a potential therapeutic strategy for OA.</p>

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Integrated bulk and single-cell transcriptomic analyses and experimental validation reveal the pathogenic role of chondrocyte pyroptosis in osteoarthritis and the therapeutic potential of curcumin via its targeted modulation

  • 期刊论文

  • 发表日期：

    2026年7月20日

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  • Juan Huang,
  • Chi Zhang,
  • Qingchuan He,
  • Yuan Chen,
  • Ruyan Chen,
  • Shibin Yang

摘要

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage destruction. Emerging evidence suggests that chondrocyte pyroptosis, a pro-inflammatory programmed cell death pathway, contributes to OA pathogenesis. However, the molecular mechanisms underlying pyroptosis in OA and potential therapeutic interventions remain incompletely understood. Bulk RNA-seq datasets (GSE114007 and GSE254844) were analyzed to identify differentially expressed genes (DEGs) and co-expression modules via DESeq2 and WGCNA. Shared key DEGs (SKDEGs) were subjected to GO and KEGG enrichment analyses to reveal relevant pathways. Pyroptosis-related DEGs (PRDEGs) were intersected with SKDEGs and used for drug prediction in EnrichR. Predicted compounds were further examined for potential targets using TCMSP, HIT, and SwissTargetPrediction databases to identify hub genes. Single-cell RNA-seq data (GSE169454) were analyzed to determine the cellular localization, differential expression, and pathway activity of hub genes. Finally, in vitro experiments with primary human normal and OA chondrocytes were performed to validate the effects of the identified compound on cell proliferation and pyroptosis. Analysis of bulk RNA-seq data identified 146 SKDEGs, with pyroptosis emerging as the most significantly enriched pathway. Six PRDEGs were identified, and curcumin was predicted as a key therapeutic compound. Intersection of curcumin targets with PRDEGs revealed four hub genes (CASP1, IL1B, IL18, NLRP3), all upregulated in OA. Single-cell analysis confirmed that these hub genes were predominantly expressed in OA-associated chondrocyte subtypes, with increased pathway activity and expression along pseudotime trajectories. In vitro, curcumin (10 µM) promoted chondrocyte proliferation and significantly suppressed the mRNA and protein expression of the hub genes, indicating inhibition of pyroptosis. Chondrocyte pyroptosis is a critical contributor to OA progression, and curcumin can alleviate OA by targeting pyroptosis-related pathways. This integrative study provides mechanistic insights and a potential therapeutic strategy for OA.