Exploring the mechanisms of PANoptosis in osteoarthritis and the therapeutic potential of andrographolide through bioinformatics and single-cell analysis.

Background: Osteoarthritis (OA) is a degenerative joint disease marked by the breakdown of cartilage, where apoptosis plays a key role. Although apoptosis-related genes in OA have been studied, a detailed analysis of PANoptosis-related genes and the search for therapeutic drugs remains limited.

Methods: We performed a bioinformatics analysis combined with single-cell RNA sequencing to examine PANoptosis-related gene expression in OA cartilage. Key PANoptosis genes and critical cell populations involved in OA progression were identified. Drug prediction led to the selection of Andrographolide (AG), whose effects were validated through molecular docking, Western blotting, and qRT-PCR in chondrocyte models.

Results: Several PANoptosis-related genes, including CASP8, TLR3, CASP1, and IL18, were significantly differentially expressed in OA. These genes are linked to processes such as apoptosis, pyroptosis, and the inflammasome complex. Pathway analysis revealed necroptosis, Toll-like receptor, and apoptosis signaling pathways as important in OA pathology. Single-cell analysis identified HomC, EC, and preHTC as key cell populations. AG was predicted to regulate PANoptosis genes, which was confirmed experimentally, demonstrating AG's potential to modulate key genes involved in cartilage degeneration.

Conclusion: This study highlights PANoptosis-related genes in OA and identifies Andrographolide as a promising therapeutic drug, offering new insights into OA treatment strategies.