Kaempferol as a dietary guardian against gastric carcinogenesis: Breaking the Correa's cascade at multiple junctions

Correa's cascade outlines the dynamic progression of gastric carcinogenesis, from chronic non-atrophic gastritis (CNAG) to chronic atrophic gastritis (CAG), gastric precancerous lesions, and finally gastric cancer (GC). A natural compound, kaempferol (KAE), abundant in many fruits and vegetables, has stimulated extensive research due to its broad range of biological activities, such as anticancer, antimicrobial, and anti-inflammatory effects. In this review, we synthesize evidence from in vitro studies and animal models to summarize the multi-target effects of KAE across Correa's cascade and the underlying pharmacological mechanisms. Available evidence suggests that KAE may exert beneficial effects across different stages of Correa's cascade, including gastric mucosal inflammation (stage 1), precancerous lesions (stage 2), and gastric cancer (stage 3). During the initial phase, KAE not only suppresses Helicobacter pylori ( Hp ) but also acts on key pathways such as nuclear factor kappaB (NF-κB)/ Activator protein-1 (AP-1), thereby inhibiting gastric mucosal inflammation. In the second stage, KAE suppresses gastric precancerous lesion progression by upregulating pro-apoptotic enzymes, enhancing antioxidant effects, and downregulating Vascular endothelial growth factor A (VEGFA) and Tumor necrosis factor (TNF). In the cancer phase, KAE counteracts GC progression by triggering autophagy, restoring redox homeostasis, and controlling the cell cycle. KAE primarily acts through the NF-κB, PI3K/Akt and MAPK signaling pathways, as well as via inflammatory mediators such as TNF-α, IL-6 and IL-10. Developing therapeutic agents such as KAE, capable of multiphasic intervention along the Correa's cascade, represents a pivotal strategy for future drug discovery.