Multi-target therapeutic potential of Flavokawain A in rheumatoid arthritis: A mechanistic and translational perspective.

Rheumatoid arthritis (RA) commonly affects synovial joints, characterised by inflammation, progressive joint destruction, and multi-organ involvement. Despite major advances in pharmacological management with DMARDs, RA remains incurable, where treatment is primarily aimed at controlling inflammation and providing symptomatic relief. Further, their long-term use is limited by significant side effects, reduced patient responsiveness, and high treatment costs. These limitations underscore the unmet need for safer and more effective alternatives with broader mechanistic coverage. The multifaceted nature of RA pathogenesis, including immune dysregulation, oxidative stress, pro-inflammatory signalling, and joint degeneration, highlights the need for medicines that can act on numerous molecular targets. Therefore, we hypothesised that flavokawain A (FKA), a naturally occurring chalcone from Piper methysticum, is a potential candidate for RA due to its multi-targeted pharmacological profile. Emerging evidence indicates that FKA can modulate key signalling pathways and inflammatory mediators, including NF-κB, PI3K/AKT, MAPK, Nrf2/ARE, mTOR, COX-2, and MMPs, in various diseases that are clinical drivers of RA progression. FKA's capacity for anti-inflammatory, antioxidant, and pro-apoptotic control may not only reduce symptoms but also affect underlying pathogenic pathways. This mechanism-based perspective review suggests FKA as a promising alternative to conventional RA therapies.