Targeting inflammatory pathways in rheumatoid arthritis management using phytochemicals and mechanistic insights.

Rheumatoid arthritis (RA) is a long-term autoimmune disease marked by inflammation of the synovial membrane, gradual joint damage and systemic issues. Contemporary treatment, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs) and biologics, usually offers symptomatic relief and suppresses immunity but is often limited by side effects and does not prevent long-term structural damage. On the other hand, phytochemicals have attracted interest as multi-target therapeutic agents that can influence key disease pathways such as NF-κB, MAPK, JAK/STAT, Nrf2/Keap1 and NLRP3 inflammasome signaling pathways. RA is driven by activation of NF-κB, MAPK, and JAK/STAT pathways, leading to excessive pro-inflammatory cytokine production and synovial inflammation. The NLRP3 inflammasome further amplifies this response via IL-1β and IL-18 activation. Conversely, impaired Nrf2/Keap1 signaling reduces antioxidant defense, aggravating oxidative stress and joint damage. Bioactive compounds including polyphenols (like curcumin, resveratrol, quercetin and epigallocatechin gallate EGCG), terpenoids (such as boswellic acids) and alkaloids (like berberine and sinomenine) along with various flavonoids, demonstrated strong anti-inflammatory, antioxidant, immunomodulatory, chondroprotective and anti-resorptive effects in early and emerging clinical studies. However, incorporating these findings into clinical practice faces challenges primarily because of suboptimal pharmacokinetics, such as poor water solubility, low gut absorption and rapid metabolism, resulting in inadequate and inconsistent levels in plasma and synovial fluid. This review integrates mechanistic and pharmacokinetic evidence to critically evaluate the potential and limitations of phytochemicals for the management of RA, and highlights advanced formulations to improve bioavailability and targeted and personalized clinical use.