Preliminary Study on the Mechanism of Arctigenin in Alleviating Osteoarthritis Pain by Suppressing Chondrocyte Pyroptosis: The Potential Role of the POU2F1/GRB10 Axis

Osteoarthritis (OA), the most prevalent form of arthritis globally, is characterized by debilitating pain driven by inflammatory and degenerative processes in chondrocytes. Here, we demonstrate that arctigenin (ATG), a bioactive lignan from Arctium lappa, alleviates OA pain by suppressing chondrocyte Pyroptosis through the POU Class 2 Homeobox 1 (POU2F1)/growth factor receptor Bound Protein 10 (GRB10) signaling axis. In a monosodium iodoacetate (MIA)-induced OA rat model, ATG administration reduced pain hypersensitivity, lowered pro-inflammatory cytokines, and elevated anti-inflammatory interleukin-10 (IL-10), while diminishing expression of Pyroptosis effectors including cleaved Caspase-1, Gasdermin-D-N (GSDMD-N), and NOD-like Receptor thermal protein domain associated protein 3 (NLRP3). In vitro studies in C28/I2 chondrocytes revealed that ATG dose-dependently attenuated inflammation and Pyroptosis markers. Mechanistically, ATG upregulated POU2F1, a transcription factor that directly binds and activates the GRB10 promoter, as confirmed by enrichment and binding assays. Silencing POU2F1 or GRB10 reversed ATG's inhibitory effects on Pyroptosis. In vivo validation further showed that ATG's pain-relieving effects in OA rats depend on this axis to curb chondrocyte Pyroptosis. Collectively, these findings highlight ATG's potential as a novel analgesic agent for OA by targeting pyroptotic pathways, offering insights into inflammation-driven pain mechanisms.