Focus on the NLRP3 inflammasome: its role in the pathogenesis and therapeutic potential of inflammation-driven osteoarthritis.

Osteoarthritis (OA) is a highly heterogeneous whole-joint disease. Current treatment strategies, which primarily focus on symptomatic pain relief, are insufficient to address the therapeutic needs of patients with distinct clinical phenotypes. Accumulating evidence has demonstrated that the empirical use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) has shown limited efficacy in OA cohorts selected on the basis of inflammatory features, underscoring the need to more precisely define inflammation-driven OA and elucidate its underlying pathogenic mechanisms. Persistent local inflammation is increasingly recognized as a prominent feature of inflammation-driven OA. Rather than being merely secondary to mechanical injury or degenerative changes, this inflammatory state is associated with sustained release of damage-associated molecular patterns (DAMPs), aberrant activation of innate immunity, and amplification of inflammatory signaling. However, no consensus criteria have been established to define inflammation-driven OA. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome integrates diverse danger signals, including extracellular ATP, crystal deposition, ionic fluxes and mitochondrial oxidative stress. Its activation promotes caspase-1 activation, the maturation and release of inflammatory cytokines, and gasdermin D (GSDMD)-mediated pyroptosis. Through cell type-specific responses and intercellular crosstalk within the OA joint microenvironment, aberrant NLRP3 inflammasome activation may sustain local inflammatory amplification, contribute to OA progression, and exacerbate joint tissue damage. In this review, we discuss the basis for stratifying inflammation-driven OA and the challenges associated with its treatment, delineate the potential pathological role of the NLRP3 inflammasome, and explore its potential as both a candidate mechanism-based biomarker and a therapeutic target. We propose that NLRP3 inflammasome activation may provide a mechanistically informative dimension for OA stratification, thereby offering a conceptual framework for moving beyond conventional symptom-oriented management toward mechanism-informed precision intervention.