Effect and Mechanism of Acacetin Against Stress‐Induced Gastric Mucosal Damage: Network Pharmacology, Molecular Docking and Experimental Verification

ABSTRACT Stress‐induced gastric ulcers (SGU) are categorized as a stress‐related mucosal disease (SRMD) that exhibits a high morbidity among ICU patients. However, due to the harmful side effects of proton pump inhibitors (PPIs), there is an urgent need for natural and proactive alternative methods in the treatment of SGU. Acacetin, a natural flavonoid, has demonstrated potential in alleviating gastric ulcers. To elucidate the effects of acacetin in SGU, in this study, gastric ulcers (GU)‐related targets were retrieved from GeneCards, DisGeNET, and OMIM. A protein–protein interaction (PPI) network was constructed, followed by functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Molecular docking was employed to predict the interactions between acacetin and key target proteins. Furthermore, a cold water‐immersion restraint stress (CWIR) induced mouse model was used to validate the protective effects of acacetin on SGU. Network pharmacology and molecular docking revealed that acacetin exerts mucosal protective effects through multiple ferroptosis‐related targets. In vivo, acacetin significantly mitigated the loss and disorganization of epithelial cells by inhibiting oxidative stress and ferroptosis, indicating its potential to protect against CWIR‐related SGU. Especially, 25 mg/kg/day might be the optimal therapeutic dosage of acacetin as an alternative treatment option for SGU.