ACE/ACE2 Steady State: A Novel Mechanism of Rosmarinic Acid in Alcohol-Associated Gastric Ulcer

Background: The local inhibition of the gastric renin angiotensin system (RAS) has emerged as a pivotal therapeutic target in treating gastric ulcers. Rosmarinic acid (RA), a medically significant herb belonging to the category of water-soluble polyphenolic compounds, exhibits notable antiulcer properties. Our previous research has demonstrated that the anti-ferroptosis effect of RA in lipopolysaccharide (LPS)-induced septic acute respiratory distress syndrome (ARDS) depends on the RAS. Therefore, this study aimed to assess the underlying mechanism through which RA mitigates ethanol-induced gastric ulcers in mice. Methods: Gastric tissue samples were collected from patients with gastric ulcers to perform RNA sequencing (RNA-seq) and bioinformatics analyses. Moreover, the gastric ulcer mouse model was induced through a single gavage of absolute ethanol at a dose of 0.1 mL/10 g. Before induction, mice were orally administered RA at doses of 4 and 20 mg/kg, or esomeprazole 3.03 mg/kg (as a reference drug), for a duration of 5 days. The anti-gastric ulcer effects were assessed through histopathological evaluations and Western blot analysis. Results: The RNA-seq data and bioinformatic insights revealed that the angiotensin-converting enzyme (ACE)/angiotensin (Ang) 2 converting enzyme (ACE2) balance may constitute a novel mechanism in alcohol-related gastric ulcer, which RA modulates. A total of six overlapping targets related to both RA and gastric ulcers were identified. Among them, matrix metalloproteinase-1 (MMP1), matrix metalloproteinase-3 (MMP3), and A Disintegrin and Metalloproteinase with a Thrombospondin type 1 motif, type 4 (ADAMTS4) presented low binding energy with RA and formed a protein-protein interaction (PPI) network with ACE and ACE2. In vivo experiments further substantiated that RA conferred gastric protection by restoring the ACE/ACE2 balance and upregulating GPX4 expression. Conclusions: RA might be a potential gastroprotective agent by suppressing RAS-related ferroptosis in the gastric tissues.