Berberine Prevents and Reverses Gastric Spasmolytic Polypeptide-Expressing Metaplasia by Modulating M2 Macrophage Polarization

Spasmolytic polypeptide-expressing metaplasia (SPEM) is a critical gastric precancerous lesion with no approved pharmacological intervention. Berberine (BBR), a natural isoquinoline alkaloid, exhibits pleiotropic anti-inflammatory and antitumor activities. This study investigated whether berberine prevents and/or reverses tamoxifen-induced SPEM in mice and elucidated the underlying mechanisms. A tamoxifen-induced SPEM mouse model was employed with berberine administered via oral gavage in both preventive and therapeutic regimens. Gastric mucosal pathology was assessed by H&E staining, immunohistochemistry, and immunofluorescence. Transcriptomic profiling, bioinformatic analyses, and single-cell RNA sequencing data integration were performed to identify key molecular targets. Berberine significantly attenuated tamoxifen-induced gastric glandular atrophy, accelerated gland recovery, and reduced the number of TFF2+ and AQP5+ SPEM cells. Transcriptomic analysis revealed that berberine reversed the tamoxifen-induced upregulation of JAK-STAT and NF-κB signaling pathways. Consistently, berberine suppressed CD163+ M2 macrophage infiltration into the gastric mucosa in a time-dependent manner. Integrative single-cell analysis identified that S100A6 expression progressively increased with malignant progression. S100A6 was also elevated in SPEM and downregulated upon berberine treatment, which might be associated with M2 macrophage infiltration. Berberine prevents and reverses gastric SPEM, at least in part, by inhibiting M2 macrophage polarization and infiltration, possibly via regulating the JAK-STAT/NF-κB pathway and S100A6 expression. These findings provide preclinical evidence supporting berberine as a candidate therapeutic agent for SPEM.