Asiatic Acid Ameliorates MNNG-Induced Chronic Atrophic Gastritis by Inhibiting the Activation of the HRAS/PI3K/AKT/GSK3β Signaling Axis.

Abstract

Chronic atrophic gastritis (CAG), a widespread gastrointestinal condition, is widely acknowledged as a precursor to gastric cancer (GC). The incidence of CAG has been steadily increasing, yet effective pharmacological interventions remain unavailable. Asiatic acid (AA), a bioactive triterpenoid isolated from Centella asiatica , has demonstrated anti-inflammatory, antioxidant, and anticarcinogenic properties in various diseases. However, its role and underlying mechanism in CAG remain poorly understood. This study sought to clarify the therapeutic potential and molecular mechanisms of AA in CAG. GES-1 cells were exposed to N-methyl-N-nitro-N-nitrosoguanidine (MNNG) to establish an in vitro CAG cell model (MC cells). Concurrently, a CAG mouse model was generated using a combination of MNNG and ethanol. Both models were treated with different concentrations of AA to evaluate its effects on HRAS/PI3K/AKT/GSK3β axis-mediated CAG. Furthermore, bioinformatics and proteomic analyses, followed by experimental validation, were applied to explore underlying mechanisms. AA significantly inhibited the proliferation and migration of MC cells and promoted apoptosis. Mechanistic studies revealed that the HRAS/PI3K/AKT/GSK3β signaling axis was aberrantly activated in CAG. In MC cells, knockdown of HRAS markedly attenuated the effect of AA; conversely, HRAS overexpression or treatment with the agonist 740Y-P partially counteracted its efficacy. In vivo experiments confirmed that AA markedly ameliorated gastric mucosal glandular atrophy, structural disorganization, and intestinal metaplasia. Furthermore, preliminary analyses suggested that AA may suppress GC progression via the same signaling pathway. AA alleviates CAG by suppressing the HRAS/PI3K/AKT/GSK3β signaling axis, thereby highlighting its therapeutic potential and providing a novel strategy for CAG treatment.