Cinnamyl Alcohol Attenuates Osteoarthritis Progression via PIGR-Mediated Regulation of Chondrocyte Senescence and Cartilage Homeostasis.

Osteoarthritis (OA) is characterized by inflammation-driven chondrocyte senescence and extracellular-matrix degradation. However, the molecular mechanisms linking inflammatory stress to chondrocyte aging remain poorly understood. Here, we identify cinnamyl alcohol (CA) as a natural small-molecule compound that attenuates OA progression through polymeric immunoglobulin receptor (PIGR)-mediated signaling in vitro. CA reduced inflammatory cytokine production, suppressed senescence-associated secretory phenotype gene expression, and preserved cartilage homeostasis in lipopolysaccharide- or interleukin-1β-stimulated chondrocytes. In a destabilization-of-the-medial-meniscus mouse model, intra-articular CA administration markedly alleviated cartilage degeneration and matrix loss. Integrating network pharmacology, molecular docking, and mass-spectrometry-based proteomic profiling, we identified PIGR as a convergent target of CA, validated by limited proteolysis (drug affinity responsive target stability) and loss-of-function assays. PIGR silencing abolished CA's antisenescent and cartilage-protective effects, confirming its essential role. Mechanistically, CA restored PIGR expression to modulate inflammatory signaling and maintain chondrocyte phenotype stability. These findings uncover a previously unrecognized CA-PIGR axis that couples inflammatory stress to cartilage aging and suggest CA as a promising natural therapeutic candidate for OA management.