| Summary: | (1) Background: Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its symptoms of joint damage and cartilage breakdown. Current treatments frequently result in adverse effects and show restricted efficacy in the long term. <i>Dendropanax morbiferus</i>, a plant recognized for its bioactive properties, demonstrates promise in the treatment of inflammatory conditions. The objective of this study was to examine the therapeutic properties of <i>Dendropanax morbiferus Lév.</i> water extract (DMWE) in RA through the utilization of in vitro and in vivo models. (2) Methods: Ultra-high-performance liquid chromatography (UPLC) analysis was used to identify bioactive compounds in DMWE. Antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical-scavenging assays. The in vitro experiments involved the treatment of CHON-001 cells with DMWE in order to assess its impacts on inflammation and matrix metalloproteinase (MMP) expression. The impact of DMWE on the Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription (STAT) signaling pathways was also assessed. RA was induced in Balb/c mice who were subsequently treated with varying doses of DMWE to assess its impact on joint morphology, edema, and body weight. (3) Results: DMWE demonstrated substantial antioxidant activity and hindered the expression of MMP-2 and MMP-8 in chondrocytes treated with IL-1β. It additionally inhibited the JAK2/STAT pathway and diminished inflammatory responses. Treatment with DMWE in living organisms led to a decrease in joint swelling, improved weight regains, and maintained joint structure, with higher doses exhibiting effects similar to those of the positive control, dexamethasone (Dexa). (4) Conclusions: DMWE was found to have excellent in vitro antioxidant and anti-inflammatory activities. In an RA-induced mouse model, DMWE-3 (500 mg/kg BW) was found to effectively treat RA by reducing the concentration of pro-inflammatory factors and preventing joint deformation.
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