Nobiletin alleviates MNNG-induced gastric injury <i>in vivo</i> and the damage of GES-1 cells in vitro through ALOX5 and PTGS2

Nobiletin is one of the citrus polymethoxyflavones and exhibits antioxidant and anti-inflammatory properties. Nobiletin is reportedly used to mitigate ethanol-induced gastric injury and to inhibit <i>Helicobacter pylori</i> infection-related gastric tumorigenesis. The present study aims to elucidate whether and how nobiletin exerts gastroprotective effects in <i>N</i>-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced chronic atrophic gastritis (CAG). In MNNG-induced Sprague-Dawley (SD) rats with CAG, we found that nobiletin dose-dependently alleviated MNNG-induced gastric histological lesions, overgeneration of inflammatory cytokines, and intestinal metaplasia. The potential targets of nobiletin in the treatment of CAG were predicted through metabolomic analysis and network pharmacology and subsequently verified by molecular docking and cell experiments. The results demonstrated that nobiletin alleviates MNNG-induced gastric epithelial cell injury and mitochondrial dysfunction by targeting arachidonate 5-lipoxygenase (ALOX5) and prostaglandin-endoperoxide synthase 2 (PTGS2). In conclusion, nobiletin alleviates MNNG-induced gastric injury <i>in vivo</i> and the damage of GES-1 cells <i>in vitro</i> via ALOX5 and PTGS2.