Targeting the NLRP3 inflammasome in rheumatoid arthritis fibroblast-like synoviocytes: pathogenic mechanisms, therapeutic strategies, and translational perspectives.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent synovitis, pannus formation, cartilage degradation, and bone erosion. Although conventional synthetic, biologic, and targeted synthetic disease-modifying antirheumatic drugs have improved disease control, many patients fail to achieve sustained remission, lose responsiveness over time, or develop treatment-limiting safety concerns. Fibroblast-like synoviocytes (FLSs) are increasingly recognized as long-lived pathogenic stromal cells that sustain synovial inflammation, promote matrix degradation, support osteoclastogenesis, and shape immune and vascular crosstalk within the rheumatoid joint. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome provides a mechanistic link between synovial stress responses and inflammatory amplification. In RA-FLSs, defined inflammatory, hypoxic and oxidative-stress conditions can induce NLRP3-related signaling, whereas other proposed triggers, including lysosomal injury, extracellular ATP and ion flux, are supported more strongly by broader synovial or general inflammasome evidence. Through caspase-1 activation, interleukin (IL)-1β and IL-18 maturation, and gasdermin D-mediated pyroptotic signaling, NLRP3 can reinforce stromal inflammation and tissue-destructive synovial remodeling. In this review, we summarize canonical, non-canonical, and alternative mechanisms of NLRP3 inflammasome activation, with emphasis on their relevance to RA-FLS biology and the inflamed synovial niche. We discuss how NLRP3 signaling intersects with fibroblast heterogeneity, macrophage-FLS crosstalk, endothelial activation, chondrocyte injury, osteoclastogenesis, and context-dependent pyroptosis. We further evaluate pharmacological strategies targeting the NLRP3 axis, including direct NLRP3 inhibitors, upstream stress modulators, caspase-1 or gasdermin D blockade, IL-1β/IL-18 pathway inhibition, natural products, repurposed molecules, nanomedicine-based delivery, and rational combination regimens. Key translational issues include FLS specificity, synovial drug exposure, target engagement, chronic safety, biomarker-guided patient selection, and mechanism-aligned endpoints. An RA-FLS-centered view of NLRP3 targeting may help refine anti-inflammatory pharmacology and support the development of synovium-directed therapeutic strategies for selected patients with difficult-to-treat RA.