Dimethyl Itaconate Attenuates Osteoarthritis by Suppressing Macrophage Chemotaxis and <scp>TLR2</scp> / <scp>NF</scp> ‐ <scp>κB</scp> / <scp>NLRP3</scp> ‐Mediated Pyroptosis: Evidence From Transcriptome and Functional Validation

Dimethyl itaconate (DMI), a permeable derivative of the immunoregulatory metabolite itaconate, exhibits potent anti-inflammatory and antioxidant properties. Its role in osteoarthritis (OA), however, remains unclear. This study demonstrates that DMI attenuates OA progression by suppressing inflammation and macrophage recruitment. In vitro, DMI mitigated IL-1β-induced inflammatory responses, cartilage matrix degradation, and NF-κB/NLRP3 pathway activation in chondrocytes. Transcriptomic analysis revealed the involvement of Toll-like receptor signaling, and functional validation identified TLR2 as a key upstream target. DMI also inhibited IL-1β-induced macrophage migration. In a rat OA model, DMI treatment alleviated cartilage destruction, synovial macrophage infiltration, and TLR2/NF-κB/NLRP3 pathway activation. These findings indicate that DMI ameliorates OA by modulating the joint microenvironment via inhibiting chondrocyte pyroptosis and macrophage chemotaxis, highlighting its potential as a novel therapeutic candidate for OA.