Sijunzi Decoction Ameliorates Ethanol-induced Gastric Ulcers: Potential Involvement of the PI3K-Akt Signaling Pathway
Le Li, Siyao Li, Yongqinq Zhu, Xiaochen Zhou, Xingjian Zhang, Di Xiao, Xiaoping YangIntroduction:
Although Sijunzi Decoction (SJZD) has demonstrated therapeutic efficacy in treating gastric ulcer (GU), its underlying pharmacological mechanisms remain insufficiently understood. This study aimed to systematically investigate the protective impacts and potential mechanisms of SJZD against ethanol-induced GU.
Methods:
Active compounds and potential targets of SJZD were identified using network pharmacology analysis. GU-related targets were collected from multiple public databases. Intersecting targets were analyzed through network construction, protein–protein interaction (PPI) analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking was performed to evaluate interactions between core compounds and key targets. Experimental validation was conducted using ethanol-induced GES-1 cell and ICR mouse models. Histopathological changes were assessed by H&E staining, and the expression levels of p-PI3K and p-AKT were determined by Western blotting.
Results:
Network pharmacology identified 247 intersecting targets, with core targets including STAT3, SRC, and AKT1. KEGG analysis identified the PI3K–Akt signaling pathway as a candidate pathway for subsequent experimental validation. Molecular docking suggested favorable binding interactions between key SJZD components (e.g., glabridin and kanzonol W) and core targets. In ethanol-injured GES-1 cells, high-dose SJZD significantly increased p-PI3K expression. In the mouse model, SJZD ameliorated gastric histopathological injury and increased the expression levels of p-PI3K and p-Akt.
Discussion:
Gastric ulcer is a necrotic lesion that may cause bleeding, perforation, or cancer. Alcohol impairs microcirculation and damages gastric mucosa. Western drugs (e.g., omeprazole) have limited efficacy with high recurrence and side effects. Traditional Chinese medicine offers advantages. Sijunzi Decoction, a classic qi‑supplementing formula for spleen‑stomach qi deficiency, reduces side effects and recurrence. Using network pharmacology, molecular docking, and in vivo/in vitro validation, this study identified 10 key targets (including STAT3, SRC, and AKT1) and the PI3K‑Akt pathway. Molecular docking showed strong binding with ≥3 hydrogen bonds. In vitro, concentrations of 1–16 mg/ml were noncytotoxic; 32 mg/ml reduced viability. High‑concentration SJZD increased p‑PI3K after ethanol injury. In vivo, SJZD alleviated ethanol‑induced acute gastric ulcer, protected gastric mucosa (HE staining), and upregulated p‑PI3K/p‑AKT (Western blot).
Conclusion:
This integrated study suggests that SJZD exerts gastroprotective effects against ethanolinduced gastric ulcer, and these effects may be associated with modulation of PI3K–Akt-related signaling.