Vaccarin ameliorates osteoarthritis by suppressing the c-Jun N-terminal kinase (JNK)-serum amyloid A2 (SAA2) pathway mediating chondrocyte senescence

• Serum amyloid A2 (SAA2) is significantly upregulated in inflamed chondrocytes, leading to mitochondrial dysfunction and increased reactive oxygen species (ROS), which aggravates inflammation and senescence. • Vaccarin effectively inhibits c-Jun N-terminal kinase (JNK) pathway activation, reduces SAA2 expression, and alleviates related cellular inflammation and senescence. • Vaccarin reduces chondrocyte inflammation and senescence, demonstrating potential as a treatment for osteoarthritis. Osteoarthritis is a chronic degenerative joint disease marked by chondrocyte senescence and extracellular matrix degradation. Vaccarin, a flavonoid with anti-inflammatory and antioxidant properties, has not been previously investigated for its therapeutic potential in osteoarthritis. To evaluate the therapeutic potential of Vaccarin in osteoarthritis and elucidate its underlying mechanisms. This study utilized in vitro chondrocyte cultures and RNA sequencing to identify relevant pathways, followed by validation at the genetic, protein, and metabolic levels using multiple approaches. Additionally, the therapeutic effects of Vaccarin were assessed in vivo using a destabilization of the medial meniscus (DMM)-induced osteoarthritis mouse model and human cartilage samples from osteoarthritis patients. Vaccarin effectively ameliorated osteoarthritis both in vivo and in vitro. Transcriptomic sequencing indicated a significant downregulation of serum amyloid A2 (SAA2) expression following Vaccarin treatment. Multi-omics analysis, validated by human specimens, indicated that SAA2 is minimally secreted in healthy articular cartilage but serves as a crucial osteoarthritis biomarker in Asian populations. Mechanistically, Vaccarin inhibits c-Jun N-terminal kinase (JNK) phosphorylation, thereby reducing SAA2 expression and mitigating chondrocyte inflammation and senescence. Notably, inflammatory conditions upregulate SAA2 expression in chondrocytes via the JNK pathway. Elevated SAA2 levels contribute to mitochondrial dysfunction in chondrocytes, leading to increased reactive oxygen species (ROS) production and exacerbating osteoarthritis progression. This study identifies SAA2 as a potential therapeutic target for osteoarthritis and suggests that Vaccarin presents a promising treatment avenue.