Effects of Fisetin and Nicorandil on adjuvant-induced rheumatoid arthritis in rats: Emerging role of TLR4/NF-κB-induced Pyroptosis, Nrf-2/HO-1, and OPG/RANKL pathways

Aim and background: Our study explored the novel mechanisms implicated in the anti-rheumatic potential of fisetin and/or nicorandil (NIC) intervention. Methods and Materials:: Fifty male rats were categorized into; control, rheumatoid arthritis (RA), fisetin-treated RA, NIC-treated RA, and co-treated RA groups. We assessed paw thickness, arthritis indices, serum CRP, RF, OPG, RANKL, and gene expressions of synovial TLR4, NLRP3, caspase-1, GSDMD, Nrf-2, and HO, along with synovial histopathology and NF-kappa B immunoreactivity. Results: The combined therapy demonstrated significantly better anti-rheumatic potential, suppressing oxidative stress and NF-kappa B, downregulating synovial TLR4, NLRP3, caspase-1, GSDMD, and increasing serum OPG while decreasing RANKL, confirmed by histopathological findings. Conclusion: Our investigation uncovered the TLR4/NF-kappa B pyroptotic signaling, Nrf-2/HO-1, and OPG/RANKL pathways as novel mechanistic insights into the anti-rheumatoid potential of fisetin and/or NIC, with superiority of combination approach, providing a beacon of hope for RA patients in terms of optimizing treatment protocol effectiveness and patient outcomes.