Integrative transcriptomics and single-cell analysis unravel the senescence-reversing mechanism of quercetin in osteoarthritic chondrocytes

BACKGROUND: Osteoarthritis (OA) is characterized by chondrocyte senescence involving inflammation, oxidative stress, and cell cycle dysregulation. Quercetin, a natural flavonoid, has multi-target potential, but its mechanism in OA chondrocyte senescence remains incompletely understood. METHODS: Integrative analysis of GSE98918 and GSE117999 transcriptomes identified OA senescence-related hub genes, followed by enrichment and immune infiltration analyses. Single-cell sequencing characterized chondrocyte subpopulations. Molecular docking and an IL-1β-induced chondrocyte senescence model (in vitro) were used to assess quercetin's effects. RESULTS: Eight hub genes (e.g., p53, CDK1, IL6) enriched in cell cycle and p53 pathways were identified. M1 macrophages infiltrated OA tissues; their secreted IL-1β/TNF-α may activate the ROS/NF-κB/p53 axis, inducing G1/S and G2/M arrest and upregulating p21. Single-cell data revealed a shift from proliferative/repair subtypes in early OA to inflammatory (InfC) and fibrotic phenotypes in late OA. In the IL-1β-induced cell model, quercetin treatment was associated with restored CDK1/CDK6 activity, reduced cell cycle arrest, downregulated IL6/TGF-β-mediated SASP, and decreased macrophage pro-inflammatory polarization, correlating with reduced p53 expression. CONCLUSION: p53-mediated cell cycle arrest and SASP-driven inflammation appear central to OA chondrocyte senescence. Quercetin targets p53 signaling and modulates oxidative stress/inflammatory microenvironments in vitro, suggesting a potential anti-senescence effect. However, in vivo validation is required before claiming cartilage degeneration delay or clinical application.