Rosmarinic acid mitigates stress-induced gastric ulcers by targeting the ACE2/GPX4 interaction.

INTRODUCTION: The renin-angiotensin system (RAS), a pivotal target in gastric ulcers, has been shown to regulate ferroptosis in bronchial epithelial cells. Rosmarinic acid (RA) possesses significant anti-ulcer and anti-ferroptosis effects. However, it is still unclear whether RA alleviates gastric ulcers by preventing ferroptosis. METHODS: We used a water restraint-induced ulcer mouse model, and an LPS-induced GEC-1 cells inflammation model to observe stress-induced damage both in vivo and in vitro, and to explore the protective effects and mechanisms of RA on such damage. RESULTS: We identified 14 DEGs related to ferroptosis between chronic gastritis and gastric ulcer. Some form a PPI network with RAS-related protein and serum ACE2 was significantly increased in ulcers. Molecular docking and molecular dynamics simulations revealed stable binding between GPX4 and ACE2, and the incorporation of RA markedly boosts its stability. Also, RA administration significantly mitigated SGU via upregulation of GPX4 and ACE2 in cold water-immersion restraint stress (CWIR) mice. DISCUSSION: Our research demonstrates that RA may be a therapeutic strategy to improve SGU by targeting the ACE2/GPX4 interaction.