Ulcerative colitis (UC) is a chronic inflammatory bowel disease lacking safe and effective long-term therapies. This study evaluated the protective effect of an aqueous fruit extract of Alchornea cordifolia in an acetic acid induced murine model of UC and investigated its phytochemical and molecular mechanisms. Oral administration of the extract (25 and 100 mg/kg) significantly reduced disease activity index, leukocyte infiltration, neutrophil recruitment, and histopathological damage, with efficacy comparable to dexamethasone. The extract markedly attenuated oxidative stress by increasing catalase and glutathione levels while reducing malondialdehyde production. Pro-inflammatory cytokines (TNF-α, IL-1β) and myeloperoxidase activity were significantly suppressed, whereas IL-10 and alkaline phosphatase activity were enhanced. LC-MS analysis identified glycosylated flavonoids, anthocyanins, and tannins as major constituents. Molecular docking and ADME analyses predicted favorable interactions between certain compounds and MPO, NLRP6, and NRF-2, thereby generating testable hypotheses regarding potential molecular mechanisms. Collectively, these findings position as the first report investigating the protective effects of A. cordifolia fruits against experimental ulcerative colitis while integrating in vivo pharmacology, LC-MS profiling and in silico analyses. Therefore, A. cordifolia fruit extract stands as a promising candidate requiring further investigation for UC management.
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