Liquiritigenin Ameliorates Rheumatoid Arthritis by Modulating the Nrf2/NF-κB/NLRP3 Pathway in Fibroblast-like Synoviocytes

Background/Objectives: Rheumatoid arthritis (RA) is an autoimmune disorder manifesting as joint destruction and synovial inflammation, with the aberrant activation of fibroblast-like synoviocytes (FLSs) functioning as a critical pathological mechanism. Liquiritigenin (LIQ), a natural flavonoid extracted from licorice root, possesses anti-inflammatory and antioxidant activities; however, its efficacy and mechanism in RA pathological models remain unclear. This study aimed to investigate the anti-RA effects of LIQ mediated through FLSs and its underlying mechanisms. Methods: Complete Freund's Adjuvant (CFA)-induced rat model and TNF-α-stimulated MH7A cell model were employed to assess the anti-RA effects and underlying mechanisms. In vivo experiments examined the effects of LIQ on RA manifestations, joint damage, and inflammatory responses in CFA-induced rats, while in vitro experiments explored its effects on aberrant activation, oxidative stress, and inflammation in TNF-α-stimulated MH7A cells. The regulatory effects of LIQ on the Nrf2/NF-κB/NLRP3 signaling pathway were validated by immunofluorescence and Western blotting in vivo and in vitro. Results: LIQ alleviated joint swelling and bone damage, reducing synovial cellular infiltration and hyperplastic changes in CFA-induced rats. Furthermore, LIQ inhibited proliferation, migration, and invasion while reducing Reactive Oxygen Species levels in TNF-α-stimulated MH7A cells, and decreased IL-1β and IL-18 levels in rat serum and MH7A cell supernatants. Moreover, LIQ activated Nrf2 and inhibited NF-κB and NLRP3, thereby attenuating inflammatory responses and alleviating oxidative stress. Administration of the Nrf2 inhibitor ML385 partially reversed its suppressive effects on inflammatory responses and oxidative stress in vivo and in vitro. Conclusions: LIQ exerted anti-RA effects in FLSs by suppressing inflammation and aberrant activation. Its mechanism may involve modulation of the Nrf2/NF-κB/NLRP3 signaling pathway.