Resveratrol Targets Multiple RA Pathways to Reduce Joint Inflammation and Damage

Rheumatoid arthritis is a chronic autoimmune disease affecting joints and multiple organ systems, with women experiencing roughly three times the incidence of men. Despite advances in disease-modifying antirheumatic drugs (DMARDs), a meaningful subset of patients responds inadequately, motivating the search for complementary therapies. Resveratrol (3,4′,5-trihydroxystilbene), a naturally occurring polyphenol abundant in grape skins, red wine, and peanuts, has attracted growing interest for its multi-target pharmacological profile.

This comprehensive 2025 narrative review by Liu and Wei synthesizes preclinical and clinical data on Res in RA, organizing findings across four major mechanistic domains: anti-inflammatory effects, oxidative stress inhibition, regulation of fibroblast-like synovial cells (FLS), and immune modulation. In antigen-induced arthritis (AIA), adjuvant arthritis (AA), and collagen-induced arthritis (CIA) animal models, Res consistently reduced paw edema, synovial hyperplasia, inflammatory cell infiltration, and cartilage destruction. Key signaling pathways suppressed by Res include NF-κB, MAPK, STAT3, Wnt, Src kinase, and MEK/ERK, while SIRT1 and Nrf2/HO-1 antioxidant pathways are upregulated.

At the cellular level, Res promotes apoptosis of RA-FLS through caspase activation (caspase-3, -8, -9 depending on model), mitochondrial dysfunction, autophagy inhibition, and endoplasmic reticulum stress. It also suppresses FLS proliferation and migration by activating the SIRT1/Nrf2 axis and reducing reactive oxygen species (ROS). On the immune side, Res reduces Th17 cell numbers and IL-17 production, inhibits B cell autoantibody production, suppresses M1 macrophage polarization, and decreases neutrophil extracellular trap (NET) formation mediated by PADI4 and COX-2.

For bone and cartilage protection, Res reduces MMP and RANKL expression via SIRT1 and PI3K/Akt pathways, limiting osteoclast formation and joint erosion. Anti-angiogenic effects are mediated through FOXO transcription factor activation (via PI3K/AKT and Ras/MEK/ERK modulation), HIF-1α suppression, and SIRT1-mediated restoration of metabolic homeostasis disrupting Rho/ROCK-driven vessel formation. Extra-articular benefits include attenuation of RA-associated interstitial lung disease (RA-ILD) and pulmonary fibrosis, and reduction of periodontal damage. Novel delivery systems—including soluble microneedles loaded with Res nanocrystals and nanoemulsion gels—show promise for improving bioavailability and local therapeutic efficacy.

Clinical trial data remain preliminary but encouraging, with early studies reporting reduced pain and improved quality of life. High oral doses (0.5–5.0 g) were generally well tolerated in healthy volunteers, with only mild, reversible gastrointestinal side effects. The authors conclude that while the mechanistic case for Res in RA is compelling, large-scale, multicenter, randomized controlled trials are essential to establish definitive efficacy, optimal dosing, and long-term safety.