Aspirin Eugenol Ester Alleviates Gastric Injury by Inhibiting Ferroptosis and Oxidative Stress

Gastric ulcer (GU) is a common upper gastrointestinal disorder characterized by oxidative stress and inflammatory responses, which significantly impact the patient's quality of life and pose a serious challenge to public health. Excessive and chronic alcohol consumption are considered primary contributing factors to gastric ulcer. Pharmacodynamic and pharmacological experiments showed that aspirin eugenol ester (AEE) had good anti-inflammatory and anti-oxidant effects. Therefore, it was speculated that AEE could alleviate ethanol-induced gastric mucosal injury through anti-inflammatory and antioxidant pathways. This study aimed to systematically evaluate the effect of AEE on ethanol-induced gastric mucosal injury using in vivo and in vitro experiments. In a gastric injury model induced by ethanol, H&E staining, AB-PAS staining, RT-PCR, immunohistochemistry, and a series of other molecular biological assays and omics techniques were employed to investigate AEE potential mechanisms. The results revealed extensive necrosis in the gastric mucosa of the ethanol group with a marked reduction in mucus secretion on the mucosal surface and a significantly decreased expression of ZO-1, claudin-1, and occludin, while AEE exhibited a significant protective effect when compared to ethanol group. AEE inhibited NF-κB pathway activation and reduced the expression of inflammatory cytokines. AEE significantly enhanced superoxide Dismutase (SOD) levels and reduced the ethanol-induced increases in reactive oxygen species (ROS), malondialdehyde (MDA), and lipid peroxidation (LPO) levels by reversing the ethanol-induced decline in Nrf-2 expression. AEE also mitigated cellular damage by inhibiting ferroptosis in the cells. AEE significantly improved the metabolic profiles of gastric tissue and serum. AEE exerts gastric protective effects by synergistically modulating multiple pathways and biological processes. AEE can enhance antioxidant capacity and inhibit ferroptosis by activating the Nrf-2/GPX4 pathway, alleviate inflammatory responses by suppressing the NF-κB pathway, and simultaneously maintain gastric mucosal barrier integrity through regulation of metabolic reprogramming and enhancement of tight junction function.