Integrative transcriptomics and single-cell analysis unravel the senescence-reversing mechanism of quercetin in osteoarthritic chondrocytes
- Biochem Biophys Res Commun. 2026 Jun 25:819:153831. doi: 10.1016/j.bbrc.2026.153831.
- 1. Department of Joint and Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong province, China; Hand and Foot Microsurgery, Shangrao Central Hospital, Shangrao City, Jiangxi Province, China.
- 2. Department of Joint and Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong province, China.
- 3. Department of Plastic Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong province, China. Electronic address: [email protected].
- 4. Department of Joint and Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong province, China. Electronic address: [email protected].
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.