Targeting NAV2-mediated Wnt/β-catenin signaling in rheumatoid arthritis: current evidence and emerging therapeutic...

Persistent activation of pathogenic signaling pathways driven by circulating mediators and intracellular factors that enhance the chronic synovial inflammation and progressive joint damage in rheumatoid arthritis (RA). Advances in the development of disease-modifying antirheumatic drugs (DMARDs) and biologics are significantly improved disease control. Still, the persistence of multidrug resistance and progressive structural damage in many reported cases indicates that multiple molecular targets in RA progression are unclear. This gap highlights the urgent need to identify new molecular pathways for next-generation therapies, which may help prevent synovial inflammation, cartilage degradation, and bone erosion arising from complex interactions among immune cells, cytokines, and dysregulated signaling pathways. The pathophysiology of RA is caused by genetic risk, environmental triggers, and dysregulated immune responses that activate fibroblast-like synoviocytes (FLS) and stimulate osteoclastogenesis. Several intracellular pathways, including JAK-STAT, PI3K-AKT, MAPK, SYK-BTK, Notch, NF-κB, and Wnt/β-catenin, play a significant role in disease progression. Among the emerging molecular pathways, NAV2-mediated modulation of Wnt/β-catenin signaling acts as a regulator for fibroblast-like synoviocyte (FLS) proliferation, cytoskeletal remodeling, and pannus formation, thereby disrupting the osteoblast-osteoclast balance and accelerating bone destruction. This identifies the NAV2-Wnt/β-catenin pathway as a promising therapeutic target for controlling structural deterioration and joint damage. In this review, we emphasize the need for a deeper understanding of interconnected molecular signaling pathways underlying RA pathogenesis, with particular focus on the NAV2-Wnt/β-catenin pathway due to its potential in reducing synovial inflammation, limiting structural damage, and improving responses to DMARDs and biologics; additionally, herbal-drug combinations may offer additive therapeutic benefits, but they require rigorous clinical validation to ensure safety and minimize adverse interactions.