Icariside II suppresses NF-κB/STAT3 signaling to prevent the progression of chronic atrophic gastritis toward gastric cancer

Chronic atrophic gastritis is a precancerous condition in the gastric carcinogenesis cascade, in which persistent inflammation plays a central role. This study aimed to evaluate the protective effects of Icariside II, a bioactive flavonoid derived from Epimedium, against inflammation-associated gastric mucosal injury. A composite mouse model was established by oral inoculation with Helicobacter pylori, administration of N-methyl-N-nitrosourea in drinking water, and a high-salt diet. Mice were randomly assigned to a model control group, an Icariside II treatment group receiving 20 milligrams per kilogram per day by gavage, or an eradication therapy group. Icariside II alleviated gastric glandular atrophy and hyperplasia and significantly reduced interleukin-6, interleukin-1 beta, and tumor necrosis factor alpha levels in both serum and gastric tissue homogenates. In human gastric cancer cells exposed to an inflammatory stimulus with tumor necrosis factor alpha, Icariside II reduced cell proliferation and migration, promoted apoptosis, and decreased the release of pro-inflammatory cytokines. Mechanistic analyses showed that Icariside II suppressed inflammation-related signaling activity by reducing phosphorylation and nuclear translocation of key transcriptional regulators, leading to decreased expression of genes involved in inflammation, cell survival, and invasion. These findings indicate that Icariside II may represent a potential natural compound for preventing or delaying the progression of chronic atrophic gastritis.