Protective effects of quercetin in experimental ulcerative colitis: Potential involvement of ERK-MMP signaling

Abstract: Background: Ulcerative colitis is a relapsing inflammatory bowel disease driven by dysregulated immunity, epithelial barrier injury and microbial imbalance. Current therapies remain limited by relapse, adverse effects and incomplete response. Quercetin has anti-inflammatory and barrier-protective activities and ERK-MMP signaling may link inflammation to mucosal tissue damage. Objectives: To evaluate whether the protective effects of quercetin in experimental ulcerative colitis (UC) are associated with modulation of ERK-MMP signaling, while avoiding causal overinterpretation beyond the animal and cellular evidence. Methods: A dextran sulfate sodium (DSS)-induced mouse model and a lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage inflammatory model were used. Mice were allocated to the control, UC model and low-, medium- and high-dose quercetin groups. Disease activity index (DAI; unitless), colon length, histopathology, inflammatory cytokines and ERK/MMP-related molecules were evaluated by histological staining, ELISA, qRT-PCR and western blotting. In-vitro, quercetin was compared with the ERK phosphorylation inhibitor U0126 and an agonistic stimulus to explore pathway-related associations. The study was exploratory and did not include genetic rescue experiments or human validation. Results: In DSS-treated mice, medium- and high-dose quercetin were associated with improved colon morphology, reduced DAI scores and partial restoration of colon length. Quercetin decreased pro-inflammatory cytokine expression and increased IL-10 expression. In both mouse colon tissues and LPS-stimulated RAW264.7 cells, quercetin was associated with reduced ERK1/2 activation and lower MMP-3 and MMP-9 expression, together with partial recovery of TIMP expression. These molecular changes were directionally consistent with the effects observed after ERK inhibition in-vitro. Conclusion: Quercetin showed protective effects in experimental UC models and these effects may be associated with modulation of the ERK-MMP signaling axis. Further pathway-specific rescue experiments, pharmacokinetic studies and human-relevant models are required before this mechanism can be considered definitive or clinically translatable.