Sakuranetin ameliorates joint inflammation and bone erosion in rheumatoid arthritis by suppressing NLRP3 inflammasome-mediated inflammatory signaling.

BACKGROUND

The selection of optimal therapeutic agents for Rheumatoid Arthritis (RA) remains a critical challenge in clinical practice. Sakuranetin (Sak), a natural flavonoid derived from Oryza sativa and Prunus species, has garnered significant attention due to its potent biological activities. However, the therapeutic potential of Sak in the treatment of RA has not yet been explored.

OBJECTIVE

This study aimed to evaluate the therapeutic efficacy of Sak against RA and to elucidate its underlying molecular mechanisms.

METHODS

A collagen-induced arthritis (CIA) mouse model was employed to assess the anti-arthritic effects of Sak in vivo. Key therapeutic targets were identified by constructing a protein-protein interaction (PPI) network, followed by enrichment analysis to predict associated signaling pathways. Furthermore, in vitro validation was conducted using Western blotting, immunofluorescence, and quantitative real-time PCR (qRT-PCR).

RESULTS

In vivo experiments demonstrated that Sak significantly ameliorated clinical symptoms in collagen-induced arthritis (CIA) mice. It reduced the levels of the pro-inflammatory cytokine IL-1β in both synovial tissue and serum, and attenuated bone erosion by suppressing IL-1β-mediated osteoclast differentiation. Network pharmacology analysis indicated that the NLRP3 signaling pathway is a pivotal mechanism underlying the IL-1β-lowering effect of Sak. Molecular docking simulations and cellular thermal shift assays (CETSA) suggested that Sak may exert its effects by directly binding to the effector proteins Caspase-1 and MMP9. In vitro assays confirmed that Sak effectively blocked NLRP3 inflammasome assembly and activation by dual-targeting both the priming and activation phases, thereby significantly suppressing IL-1β production.

CONCLUSION

Our findings suggest that Sak represents a promising therapeutic candidate for the management of RA.