Gastroprotective [6]-Gingerol Aspirinate as a Novel Aspirin-Derived Chemopreventive Agent Attenuating Colitis.

Daily low-dose aspirin reduces cardiovascular disease and colorectal cancer risk, but it is limited by gastrointestinal toxicity. To enhance safety and efficacy, we developed [6]-gingerol aspirinate (GAS) by conjugating aspirin with ginger-derived bioactive [6]-gingerol. This study evaluated GAS in a dextran sodium sulfate (DSS)-induced colitis mouse model. GAS significantly improved clinical symptoms and reduced pro-inflammatory markers (IL-6, TNF-α, IL-1β, TGF-β, and COX-2), whereas aspirin alone showed minimal protection. Untargeted LC/MS-based metabolomics revealed that GAS reversed 73 DSS-altered metabolites, including those related to lipids, amino acids, and carbohydrate metabolisms, many previously linked to inflammatory bowel disease and colorectal cancer. Correlation analysis showed strong associations between these metabolites and inflammatory cytokines, suggesting their involvement in GAS-mediated anti-inflammatory effects. Overall, GAS provides superior protection against colitis through coordinated suppression of inflammation and modulation of disease-associated metabolic pathways, highlighting its potential as a safer chemopreventive agent and identification of candidate metabolic biomarkers.