ETHNOPHARMACOLOGICAL RELEVANCE:Chronic atrophic gastritis (CAG) is a common and frequently occurring disease of the digestive system. Shengyang Xiehuo Formula (SYXHF) is a classical prescription originating from Li Dongyuan's "Treatise on Spleen and Stomach". In recent years, SYXHF has garnered widespread attention for its therapeutic effects on chronic atrophic gastritis, although its specific mechanisms of action require further investigation.
AIM OF THE STUDY:This study employed a combined approach integrating network pharmacology, molecular docking, molecular dynamics simulations, and in vitro/in vivo experimental validation to investigate the therapeutic efficacy of SYXHF on CAG and its underlying mechanisms.
MATERIALS AND METHODS:This study analyzed the active components of SYXHF through ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and employed network pharmacology, molecular docking, and molecular dynamics simulation techniques to identify and validate the interactions between the active components of SYXHF and disease targets. The N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) combined with ranitidine compound modeling approach was utilized to induce CAG model in mice, thereby verifying the therapeutic efficacy of SYXHF. MNNG-induced injured gastric mucosal epithelial cells were employed to investigate how SYXHF mediates the TNF-α/PPARγ axis to influence lipid droplet-mitochondrial interactions.
RESULTS:UPLC-MS/MS revealed that the main active components of SYXHF include quercetin, decursin, berberine, isoferulic acid, kaempferol, calycosin, baicalin, β-sitosterol, and saikosaponin A. Network pharmacology analysis identified a total of 211 active SYXHF compounds and 373 potential targets. Key targets included STAT3, TP53, JUN, AKT1, IL-6, TNF, and PPARG. Molecular docking and molecular dynamics simulations further validated the interaction relationships between compounds quercetin, kaempferol, and target proteins TNF and PPARG. In vitro and in vivo experiments demonstrated that SYXHF inhibits the PLIN2/ACSL1 interaction by modulating the TNF-α/PPARγ axis, effectively alleviating inflammation, suppressing lipid droplet-mitochondrial interaction, promoting lipid droplet lipolysis to mitigate gastric mucosal pathological damage, and thereby inhibiting the progression of CAG.
CONCLUSION:SYXHF inhibits the interaction between PLIN2 and ACSL1 via the TNF-PPARG pathway, regulating lipid droplet-mitochondrial interaction to promote lipid droplet lipolysis, which may represent a novel approach to halt the progression of CAG.