Gastroprotective effect of Daphniphyllum calycinum Benth.–Polygonum hydropiper L. against gastric mucosal injury through autophagy activation and apoptosis suppression

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ETHNOPHARMACOLOGICAL RELEVANCE: Gastric mucosal injury, commonly induced by ethanol and psychological stress, represents a significant clinical challenge with limited natural therapeutic options. The Li ethnic herbal pair consisting of Daphniphyllum calycinum Benth. and Polygonum hydropiper L. (DCPH), commercially available as Fengliao Changweikang Granules, is traditionally used by the Li people of Hainan, China, for gastrointestinal disorders. However, its gastroprotective effects and underlying mechanisms remain to be systematically characterized. AIM OF THE STUDY: This study aimed to investigate the protective effects of DCPH and its functional associations with autophagy and apoptosis pathways in ethanol-induced gastric mucosal injury models. MATERIALS AND METHODS: The chemical profile of DCPH-containing serum was analyzed using HPLC-MS. Network pharmacology and molecular docking were performed to predict candidate components and putative protein interaction partners. Protective effects were evaluated in ethanol-induced gastric injury models in KM mice and human gastric epithelial GES-1 cells. Gastric mucosal morphology, ulcer index, histopathology (H&E staining), apoptosis (TUNEL, flow cytometry), and autophagy markers (Beclin1, LC3-II/I, P62) were assessed. Transcriptomic and metabolomic analyses were conducted to explore regulatory pathways. RESULTS: HPLC-MS identified 86 compounds in DCPH-containing serum, including flavonoids and alkaloids. Molecular docking revealed predicted strong binding affinities (<-7.0 kcal/mol) between key components (quercetin, kaempferol, caldaphnidine C) and apoptosis/autophagy-related proteins (BAX, Bcl-2, CASP3, Beclin1, LC3, P62), suggesting potential interactions that warrant further experimental validation. In vivo, DCPH significantly reduced gastric mucosal congestion, edema, and ulcer index, with the high-dose effect comparable to omeprazole. DCPH treatment was associated with upregulated Beclin1 and LC3-II/I and downregulated P62; these effects were partially reversed by chloroquine. DCPH treatment was also associated with reduced apoptosis, coinciding with modulation of BAX/Bcl-2/Cleaved Caspase-3 expression. Integrated omics analyses indicated regulation of lipid metabolism, glycolysis, and inflammatory pathways. CONCLUSIONS: DCPH demonstrates protective effects against ethanol-induced gastric mucosal damage that are functionally associated with modulation of autophagy markers and apoptosis-related proteins. These findings support further investigation into the traditional use of this herbal pair and its potential as a natural therapeutic candidate, pending clinical validation and direct target confirmation.

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