Yiwei Xiaoyu granules mitigate spasmolytic polypeptide-expressing metaplasia-associated gastric mucosal damage by regulating WFDC2 and the miRNA-7/circRNA network
BACKGROUND Gastric cancer develops through a sequence of atrophy, metaplasia, and dysplasia. Spasmolytic polypeptide-expressing metaplasia (SPEM) is a pivotal precancerous lesion associated with inflammation and noncoding RNA dysregulation. In traditional Chinese medicine (TCM), these pathological changes overlap with spleen-stomach deficiency syndrome (SSDS). Yiwei Xiaoyu granules (YWXY), a classical TCM formula, have demonstrated clinical benefit in chronic atrophic gastritis, yet their mechanistic actions in SPEM combined with SSDS remain unclear. AIM To investigate the protective effects and mechanisms of YWXY in a tamoxifen-induced SPEM and SSDS composite model. METHODS A mouse model of tamoxifen-induced SPEM, with or without SSDS, was established. The effects of YWXY on gastric mucosa were evaluated by histological scoring, quantitative polymerase chain reaction (qPCR), and fluorescence in situ hybridization (FISH). Key molecular endpoints included inflammatory cytokines [interleukin (IL)-1β and tumor necrosis factor (TNF)-α], the miR-7a-5p/Cdr1as axis, and the metaplastic marker WFDC2. Statistical analysis was performed using two-way analysis of variance followed by Tukey’s multiple comparisons. RESULTS YWXY exhibited time-dependent modulation of IL-1β, normalizing its expression at day 15 and suppressing persistent elevation at day 30. TNF-α overexpression in SPEM was significantly reduced by YWXY at both time points. Cdr1as downregulation in pathological groups was partially reversed by YWXY, while miR-7a-5p suppression in SSDS and SPEM + SSDS was restored toward baseline. WFDC2 induction in both SPEM and SSDS was significantly attenuated by YWXY, confirmed by qPCR and FISH. These findings indicate coordinated regulation of inflammatory cytokines, ncRNA networks, and metaplastic markers. CONCLUSION YWXY alleviates gastric mucosal injury in combined SPEM and SSDS by regulating IL-1β and TNF-α, restoring the miR-7a-5p/Cdr1as axis, and suppressing WFDC2 expression.