Scopoletin Mitigates DSS‐Induced Ulcerative Colitis by Attenuating NF‐κB/MMP‐9 Mediated Inflammation and Activating the Nrf2 Pathway to Preserve Colonic Barrier Integrity

ABSTRACT Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon, characterized by persistent mucosal inflammation and epithelial barrier disruption. This study investigated the therapeutic efficacy of Scopoletin, a natural coumarin derivative with established anti‐inflammatory and antioxidant properties, in a DSS‐induced colitis model in Balb/c mice. A total of five experimental groups were established: a normal control, a DSS+ vehicle group, two Scopoletin‐treated groups (10 and 30 mg/kg), and a reference group treated with Sulfasalazine (200 mg/kg). Network pharmacology analyses identified key inflammatory and immune‐regulatory pathways potentially modulated by Scopoletin. In vivo assessments encompassed body weight monitoring, DAI scoring, colon length measurement, and histopathological evaluation using H&E, PAS, and Alcian blue staining. Scopoletin (30 mg/kg) treatment significantly ameliorated clinical and histological manifestations of colitis, including body weight loss and colonic shortening. Mechanistically, Scopoletin (30 mg/kg) attenuated the expression of pro‐inflammatory cytokines such as TNF‐α and IL‐1β, suppressed NF‐κB activation, MMP‐9, COX‐2 and enhanced the Nrf2 expression, leading to upregulation of antioxidant enzymes HO‐1 and NQO1. Notably, Scopoletin (30 mg/kg) restored the expression of tight junction proteins such as Occludin and ZO‐1, indicating reinforcement of epithelial barrier integrity. These findings demonstrated that Scopoletin protects against UC by suppressing inflammation, enhancing antioxidant defenses, and preserving mucosal barrier integrity, highlighting its potential as a therapeutic candidate for UC.