Macrophage NOX4/ROS–NLRP3 signaling and metabolic reprogramming in gastric premalignant lesions: microbial extracellular vesicles as candidate persistent triggers

Gastric carcinogenesis proceeds through a multistep cascade in which chronic Helicobacter pylori infection drives chronic atrophic gastritis (CAG), spasmolytic polypeptide-expressing metaplasia (SPEM), intestinal metaplasia (IM), and dysplasia before invasive adenocarcinoma emerges. Although H. pylori eradication lowers cancer incidence, a substantial residual risk persists in successfully treated individuals, and metachronous gastric cancer continues to arise within a field of atrophic and metaplastic mucosa. This review examines the contribution of macrophages to this residual risk, focusing on a signaling axis in which inducible NADPH oxidase 4 (NOX4)–derived reactive oxygen species (ROS) licenses glycolytic reprogramming that supports NLRP3 inflammasome activation and sustained IL-1β release. We discuss how bacterial extracellular vesicles (EVs), including H. pylori outer membrane vesicles (OMVs) and vesicles shed by a dysregulated gastric microbiota, may provide a protected source of microbial stimuli that could help maintain this program after the original pathogen has been cleared; whether H. pylori-derived vesicles persist after eradication, or are replaced by vesicles produced de novo by the residual non-H. pylori microbiota, has not been determined. We further consider trained immunity as a working framework for persistent macrophage responsiveness, distinguishing short-lived priming of circulating monocytes from durable tissue or progenitor memory, while noting that direct evidence for gastric mucosal trained immunity remains limited. The downstream consequences for chief-cell transdifferentiation into SPEM, stromal remodeling, and the gradual loss ofprotective folate receptor β (FOLR2)-positivemacrophages are reviewed, together with the therapeutic implications of NOX4-directed inhibition, NLRP3 blockade, and metabolic interference. We conclude that intervening on the macrophage NOX4/ROS–metabolic–NLRP3 axis, rather than on bacterial burden alone, may help address the residual gastric cancer risk that persists after H. pylori eradication.