Helicobacter pylori-induced ADAMDEC1 overexpression in M2 macrophages drives preneoplastic progression in the gastric mucosa.

Helicobacter pylori ( H. pylori) infection is a major risk factor for gastric cancer, though the immune microenvironmental factors driving preneoplastic transformation remain unclear. In this study, single-cell RNA sequencing was used to characterize macrophage subsets and identify key genes associated with H. pylori-induced gastric lesions. Molecular, cellular, and in vivo assays were conducted to determine the mechanisms regulating the expression of a disintegrin and metalloproteinase-like decysin 1 ( ADAMDEC1) and its downstream effects. M2 macrophages were significantly enriched in H. pylori-positive gastritis and metaplasia, and ADAMDEC1 showed progressive increase in expression during lesion progression. H. pylori promoted M2 polarization and induced ADAMDEC1 transcription via signal transducer and activator of transcription 3 (STAT3) binding to its promoter. Functionally, M2-derived ADAMDEC1 increased soluble epidermal growth factor levels, thereby activating the epidermal growth factor receptor (EGFR)-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway in epithelial cells, which led to upregulation of C-C motif chemokine ligand 20 (CCL20) expression, enhanced proliferation, and impaired genomic stability. The present study reveals a potential H. pylori-driven oncogenic pathway involving the M2 macrophage-ADAMDEC1-EGF/EGFR/ERK axis, establishing ADAMDEC1 as a potential target for early intervention in H. pylori-associated gastric cancer.