Bezafibrate, a Pan PPAR agonist, attenuates experimental rheumatoid arthritis via PPAR dependent modulation of inflammatory pathways with emphasis on PPAR γ activity.

Peroxisome proliferator-activated receptor gamma (PPAR-γ) plays a key role in immunoregulatory functions, making it a promising target for distinct inflammatory diseases, including rheumatoid arthritis. In the present study, we aimed to identify and evaluate a clinically viable PPAR-γ agonist with anti-arthritic potential using a structure-based drug repurposing approach. Initially, molecular docking was performed using a panel of fibrate-class compounds (including pemafibrate, bezafibrate, fenofibrate, gemfibrozil, and clofibrate) against the ligand-binding domain of PPAR-γ (PDB ID: 7WGO). Pemafibrate demonstrated the highest binding affinity; however, it exhibited poor ADMET properties, including predicted hepatotoxicity and poor intestinal absorption. Bezafibrate, on the other hand, demonstrated good binding affinity and a superior ADMET profile, and was therefore selected for further in vivo assessment. In the preclinical phase, bezafibrate (30 mg/kg/day, oral) was evaluated in a collagen-induced arthritis rat model. Disease progression was monitored through body weight analysis and hind paw and knee joint thickness measurements over 5 weeks. Histological examination of joint tissue and serum cytokine profiling (IL-1β, TNF-α, IL-6) were performed to evaluate tissue damage and inflammation. Bezafibrate significantly attenuated arthritic symptoms, preserved joint integrity, and reduced systemic inflammatory markers. RT-qPCR analysis revealed downregulation of pro-inflammatory transcription factors like NF-κB and AP-1 in synovial tissues, supporting its underlying mechanism of action. These findings suggest that bezafibrate, selected through integrative computational and pharmacological screening, effectively ameliorates experimental autoimmune arthritis via PPAR-γ activation. This highlights its promise as a repurposed therapeutic candidate and warrants further investigation.