Emodin delays rheumatoid arthritis progression by inhibiting the ROS/TXNIP/NLRP3 signaling pathway

Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting small joints of the hands, feet, and ankles, causing synovitis, pannus formation, and vasculitis. RA can lead to joint destruction and multi-system complications. Emodin (EMO), the primary active component of rhubarb, has significant anti-inflammatory properties and therapeutic potential in alleviating RA symptoms. This study focused on this therapeutic efficacy and underlying mechanisms. Collagen-induced arthritis (CIA) mouse models and lipopolysaccharide (LPS)-stimulated RAW264.7 cells were used to investigate the effects of EMO on pathological markers, inflammatory factors, and oxidative stress through histopathological analysis, western blotting, micro-computed tomography (CT), and immunohistochemistry (IHC). Proteomics, molecular docking, and molecular dynamics (MD) simulations were used to identify key targets and to elucidate the mechanisms of action underlying the therapeutic efficacy of EMO. EMO alleviated joint swelling, reduced arthritis scores, and mitigated bone damage in mice with CIA. EMO significantly decreased inflammatory factor levels and attenuated oxidative stress, as shown through reduced reactive oxygen species (ROS) and malondialdehyde (MDA) levels and increased superoxide dismutase (SOD) activity. EMO inhibited inflammasome activation, as indicated by reduced NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), interleukin (IL)-1β, and IL-18 expression. The analyses showed that the anti-inflammatory effects of EMO are mediated through ROS/TXNIP/NLRP3 signaling pathway inhibition. Collectively, EMO downregulated inflammatory responses and oxidative stress, inhibited inflammasome activation, and alleviated RA symptoms through ROS/TXNIP/NLRP3 signaling pathway suppression. These findings highlight its potential for RA treatment and provide insights into its mechanisms and clinical applications.