Abstract

Background Ulcerative colitis (UC) is a long-term, recurrent inflammatory condition marked by bloody feces and mucosal damage. Its rising global incidence and socioeconomic burden necessitate safer long-term interventions. Edible and medicinal herbs (EMHs) are prospective alternatives due to their multi-target profiles and safety. Eleutheroside E (EE), a key component of the well-known EMH Eleutherococcus senticosus , exhibits robust inflammation-suppressing capacities. Nonetheless, its anti-inflammatory protective efficacy and associated mechanisms in acute colitis require further exploration. Purpose This study endeavored to delineate the anti-inflammatory protective effects and associated molecular cascades of EE in ameliorating DSS-induced acute colitis. Methods The anti-inflammatory protective properties of EE were evaluated in a dextran sulfate sodium (DSS)-induced colitis model under simultaneous administration conditions. The functional reliance and target engagement of the MAPK pathway were comprehensively explored in vivo and in vitro using specific inhibitors (SCH772984), an agonist (Ro 67-7476), small interfering RNA (siRNA) knockdown, and Cellular Thermal Shift Assay (CETSA). Protective efficacy, the inflammatory microenvironment, Th17 immune responses, and gut microbiota profiles were assessed via histopathological scoring, ELISA, RT-qPCR, Western blotting, flow cytometry, RNA-seq, and 16S rRNA sequencing. Results Under simultaneous administration, EE intervention effectively alleviated DSS-mediated body weight reduction, disease progression and colonic atrophy, and relieved intestinal mucosal lesions. Secondary to the attenuation of local inflammation, EE maintained the intact intestinal barrier structure. Molecularly, CETSA confirmed that EE physically targets and stabilizes MAPK kinases (MEK1/ERK2). In vitro, targeted siRNA silencing of MEK/ERK in LPS-stimulated RAW264.7 macrophages abolished the further anti-inflammatory effects of EE, confirming