Graphical Abstract.

Overview of the mechanistic basis for Gent-mediated treatment of rheumatoid arthritis. Stimulation of cells with TNF-α leads to both NF-κB activation and ROS production, thereby driving NLRP3, ASC, pro-caspase-1, and pro-IL-1β upregulation. In response to the above signal, the NLRP3 inflammasome then undergoes assembly and cleavage of pro-caspase-1 to yield an active form of this protein, thus forming the NLRP3 inflammasome which then cleaves pro-IL-1β into mature IL-1β that is subsequently secreted from stimulated cells. This IL-1β subsequently promotes RA progression. Gent was able to inhibit ROS-NF-κB activation and to disrupt NLRP3 inflammasome assembly, thereby reducing IL-1β secretion. This in turn resulted in decreased RA-FLS migration and proliferation, thus significantly decreasing the severity of RA immunopathological injury.