POS0433 POTENTIAL THERAPEUTIC EFFECTS OF NARINGENIN ON RA THROUGH SUPPRESSING P2X7R/NLRP3 MEDIATED PYROPTOSIS BY TARGETING ESR

Background Naringenin (NAR), a partial agonist on estrogen receptor, is naturally occurring flavonoids in grapes and grapefruits. We previously reported that NAR in patients with Rheumatoid arthritis (RA) have changed significantly [1]. However, the role and mechanism of action of NAR in RA remain unclear. Objectives This study aimed to determine the roles and mechanisms of NAR on RA and provides a basis for NAR to become a potential therapeutic agent for RA. Methods This study employed bovine type II collagen-induced arthritis (CIA) rats, in vitro mononuclear cells (MNCs) as models to explore the potential therapeutic effects and mechanisms of NAR on RA. Results Rats following NAR injections showed significantly alleviated CIA, while the proportion of NK cells decreased. After CIA rats were injected with both NAR and NK cells, the rats remained joint inflammation. NAR decreased the proportion of NK cells in RA MNCs. However, NAR did not directly affect the NK cell activation and their cytokine production. NAR suppress pyroptosis in THP-1 cells (Figure 1). The NAR activate the ESR1 in macrophage. NAR significantly increased histone deacetylase 1 gene (HDAC1) activation in macrophage. NAR significantly increased P2X7R expression and decreased NLRP3 expression in macrophage. Figure 1. Effect of NAR on RA in vitro and in vivo. A The chemical structures of NAR and Estrogen. B Flow cytometry assay of NK cells in MNCs with treatment of NAR. C The morphology of THP-1 cells with treatment of NAR. D Joint inflammation of CIA rats with treatment of NAR and NK cells. E The expression level of pyroptosis -related protein was tested by western blot (WB). F Pattern diagram explaining therapy mechanism of NAR to RA. Conclusion NAR has therapeutic effects for CIA and RA through suppressing P2X7R/NLRP3 mediated pyroptosis by targeting ESR. References [1]Wang H, Fang K, Wang J, Chang X. Metabolomic analysis of synovial fluids from rheumatoid arthritis patients using quasi-targeted liquid chromatography-mass spectrometry/mass spectrometry. Clinical and experimental rheumatology. 2021;39(6):1307-1315. Acknowledgements Natural Science Foundation of Shandong Province (ZR2021QH329). Disclosure of Interests None declared.