Evodiamine Regulates Oxidative Stress and the JAK2/STAT3 Pathway to Modulate Apoptosis, Inflammation, Cell Cycle Arrest, and Migration in Periodontal Ligament Cells

Periodontitis represents a primary etiological factor in tooth mobility, with oxidative stress contributing critically to periodontal tissue destruction. Evodiamine (EVO), a quinazolinocarboline alkaloid, exhibits multiple biological activities; however, its antioxidant effects and mechanism in periodontitis have not been elucidated. The aim of this study was to investigate the regulatory effect of EVO on oxidative stress in periodontitis and to explore the associated molecular mechanism. The results indicate that EVO exhibits potent antimicrobial activity against key periodontal pathogens and suppresses pathogen-induced ROS generation as well as the release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) under periodontitis conditions. EVO binds specifically to the Kelch domain of KEAP1 with a strong binding energy (-11.67 kcal/mol), inhibits KEAP1-NRF2 interaction, and consequently upregulates the expression of antioxidant enzymes (HO-1, NQO1, GCLC, and SOD2), while downregulating the expression of iNOS, COX2, and NOX2. Furthermore, EVO inhibits the pro-apoptotic effect of the JAK2/STAT3 signaling axis and mitigates inflammation, alleviates cell cycle arrest, and promotes the migration and repair of periodontal ligament cells. Collectively, these findings suggest that EVO acts as a potential binder of KEAP1 that alleviates periodontal inflammation through modulation of oxidative stress and regulation of the JAK2/STAT3 pathway.