Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Renqingchangjue ameliorates MNNG-induced chronic atrophic gastritis by inhibiting the TNF/NF-κB/Caspase-3 axis.
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Chen Yuan, Yue Guang, Liu Yanjun, Wang Wei, Jiang Ge, Zhang Jinhua, Ga Zhuo, Zhang Yanfei, Liu Xiaoya, Ren Qingjia, Li Caolong
Аннотация
BACKGROUND: Chronic atrophic gastritis (CAG) is a pivotal premalignant stage in the Correa cascade, characterized by progressive and largely irreversible loss of gastric glands and an elevated risk of gastric cancer. Renqingchangjue (RQCJ), a classical Tibetan multi-herb formula, has demonstrated clinical and pharmacological benefits in gastritis, yet its mechanisms of action in CAG remain inadequately defined.
PURPOSE: This study aims to clarify the therapeutic efficacy and mechanistic basis of RQCJ in CAG.
METHODS: We established a network pharmacology-bioinformatics workflow to predict potential RQCJ targets in CAG, integrating targets obtained from TCMSP/SwissTargetPrediction with CAG-related genes to construct a STRING protein-protein interaction (PPI) network and perform GO/KEGG enrichment analyses. Constituents were characterized by UHPLC-HRMS/MS. An MNNG-induced CAG mouse model (control group, model group, Weifuchun positive control group, RQCJ low-dose group and RQCJ high-dose group) was validated by histopathology (H&E), immunohistochemistry (IHC), immunofluorescence (IF), TUNEL, ELISA, and Western blot (WB). In vitro, MNNG-injured GES-1 cells were evaluated using CCK-8, scratch wound-healing, and Annexin V-FITC/PI flow cytometry. Mechanistically, RT-qPCR, WB, and reference-based transcriptome sequencing of gastric tissue were employed, and compound druggability was assessed by AutoDock Vina docking.
RESULTS: RQCJ markedly ameliorated MNNG-induced chronic atrophic gastritis in vivo and in vitro. UHPLC-HRMS/MS profiling identified 43 constituents, of which 31 were detected as circulating prototypes. Network pharmacology first predicted 154 putative RQCJ-CAG targets enriched in TNF/NF-κB signaling; integrating serum-absorbed component targets with CAG-related genes refined this to 140 high-confidence targets with consistent TNF/NF-κB enrichment. Functionally, RQCJ (20-40 μg/mL) improved GES-1 cell viability and migration while suppressing apoptosis, and in mice dose-dependently repaired gastric mucosal architecture, lowered TNF-α, IL-1β and IL-6, and normalized gastrin and pepsinogen. RQCJ also reduced IL-8, CCL2 and CXCL1 mRNA and increased IL-10 in both models. Mechanistically, it inhibited phosphorylation of IKKβ, IκBα and NF-κB p65 in a dose- and time-dependent manner, decreased cleaved caspase-8/3, restored the Bax/Bcl-2 ratio. Transcriptomics confirmed enrichment of NF-κB and apoptosis pathways, and intersecting differentially expressed genes with the 140 serum-based targets yielded 99 core genes converging on TNF/NF-κB-mediated apoptosis. Molecular docking further supported target engagement, with a chromen-7-ol derivative showing strong predicted affinity for MMP9.
CONCLUSIONS: Together, these multi-level data indicate that RQCJ exerts clinically relevant protection against CAG via multi-component suppression of TNF-NF-κB/Caspase-3 axis, broad rebalancing of pro-/anti-inflammatory cytokines, and restoration of gastric function.
PURPOSE: This study aims to clarify the therapeutic efficacy and mechanistic basis of RQCJ in CAG.
METHODS: We established a network pharmacology-bioinformatics workflow to predict potential RQCJ targets in CAG, integrating targets obtained from TCMSP/SwissTargetPrediction with CAG-related genes to construct a STRING protein-protein interaction (PPI) network and perform GO/KEGG enrichment analyses. Constituents were characterized by UHPLC-HRMS/MS. An MNNG-induced CAG mouse model (control group, model group, Weifuchun positive control group, RQCJ low-dose group and RQCJ high-dose group) was validated by histopathology (H&E), immunohistochemistry (IHC), immunofluorescence (IF), TUNEL, ELISA, and Western blot (WB). In vitro, MNNG-injured GES-1 cells were evaluated using CCK-8, scratch wound-healing, and Annexin V-FITC/PI flow cytometry. Mechanistically, RT-qPCR, WB, and reference-based transcriptome sequencing of gastric tissue were employed, and compound druggability was assessed by AutoDock Vina docking.
RESULTS: RQCJ markedly ameliorated MNNG-induced chronic atrophic gastritis in vivo and in vitro. UHPLC-HRMS/MS profiling identified 43 constituents, of which 31 were detected as circulating prototypes. Network pharmacology first predicted 154 putative RQCJ-CAG targets enriched in TNF/NF-κB signaling; integrating serum-absorbed component targets with CAG-related genes refined this to 140 high-confidence targets with consistent TNF/NF-κB enrichment. Functionally, RQCJ (20-40 μg/mL) improved GES-1 cell viability and migration while suppressing apoptosis, and in mice dose-dependently repaired gastric mucosal architecture, lowered TNF-α, IL-1β and IL-6, and normalized gastrin and pepsinogen. RQCJ also reduced IL-8, CCL2 and CXCL1 mRNA and increased IL-10 in both models. Mechanistically, it inhibited phosphorylation of IKKβ, IκBα and NF-κB p65 in a dose- and time-dependent manner, decreased cleaved caspase-8/3, restored the Bax/Bcl-2 ratio. Transcriptomics confirmed enrichment of NF-κB and apoptosis pathways, and intersecting differentially expressed genes with the 140 serum-based targets yielded 99 core genes converging on TNF/NF-κB-mediated apoptosis. Molecular docking further supported target engagement, with a chromen-7-ol derivative showing strong predicted affinity for MMP9.
CONCLUSIONS: Together, these multi-level data indicate that RQCJ exerts clinically relevant protection against CAG via multi-component suppression of TNF-NF-κB/Caspase-3 axis, broad rebalancing of pro-/anti-inflammatory cytokines, and restoration of gastric function.