Decoding inflammatory mediators in the Correa's cascade: From chronic gastritis to carcinogenesis and targeted therapies

Gastric cancer (GC) stands as one of the most prevalent malignant tumors worldwide, with its pathogenesis remaining incompletely elucidated. Correa's cascade delineates a sequential progression from normal gastric mucosa through chronic gastritis, atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia, ultimately culminating in adenocarcinoma. Inflammation serves as the initiating phase of this cascade, predominantly triggered by Helicobacter pylori (H. pylori) infection. H. pylori induces substantial production of inflammatory mediators, including cytokines, chemokines, growth factors, and others. These mediators orchestrate multi-step regulation of Correa's cascade through mechanisms encompassing recruitment and infiltration of inflammatory cells, oxidative stress, dysregulation of cell proliferation and apoptosis, immunosuppression/immune evasion, angiogenesis, epithelial-mesenchymal transition (EMT), and tumor invasion and metastasis. This study represents the first systematic investigation comprehensively elucidating the specific mechanisms through which inflammatory mediators promote Correa's cascade progression. Furthermore, we explore the therapeutic potential of novel intervention strategies targeting inflammatory mediators across multiple stages, including natural products, cytokine antagonists, and emerging nanotechnology-based approaches, which may enable reversal of Correa's cascade. These findings provide new insights for developing preventive and therapeutic regimens against gastric carcinogenesis.