Mechanism of Xiaojianzhong decoction in alleviating aspirin-induced gastric mucosal injury revealed by transcriptomics and metabolomics

Aspirin, as a first-line drug for the treatment of cardiovascular diseases, currently has high clinical usage. However, reports of aspirin-induced gastric mucosal injury are increasing. Xiaojianzhong decoction (XJZD), a classic traditional Chinese medicine formula, has been shown to alleviate gastric mucosal injury, although its potential mechanism of action requires further study. This study aimed to explore the effect and mechanism of XJZD in preventing aspirin-induced gastric mucosal injury. Aspirin was used to induce damage in the morning, while XJZD was applied as an intervention in the afternoon. The compounds in the XJZD were analyzed by means of both high-performance liquid chromatography and ultra-performance liquid chromatography–tandem mass spectrometry. The overall condition of the aspirin-related gastric mucosal injury was evaluated. The expressions of inflammatory factors and tight-junction-related proteins and apoptosis were observed via immunohistochemistry and immunofluorescence. The expression levels of the apoptosis-related proteins were detected using Western blot. Transcriptomics was used to perform the integrative analysis of gastric tissues, which was then validated. Molecular dynamics was used to explore the interaction of key compounds within the XJZD with relevant targets. Finally, non-targeted metabolomics was used to observe any metabolic changes and construct a network between the differentially expressed genes and the differential metabolites to elucidate their potential relationship. XJZD can alleviate inflammation response, maintain the gastric mucosal barrier's integrity, reduce apoptosis and necroptosis levels, and promote the proliferation and repair of gastric mucosal tissues. Its mechanism of action may be related to the regulation of TNF-α signaling. Furthermore, molecular docking showed that the cinnamaldehyde within XJZD played an important role in its effects. In addition, XJZD can correct metabolic disorders, mainly regulating amino acid metabolism pathways. Moreover, six differential genes (Cyp1a2, Cyp1a1, Pla2g4c, etc.) were determined to alleviate both gastric mucosal injury and inflammation by regulating arachidonic acid metabolism, Tryptophan metabolism, etc. This study is the first to report that XJZD can inhibit necroptosis and gastric mucosal injury induced by aspirin, thereby revealing the complex mechanism of XJZD in relation to alleviating gastric mucosal injury from multiple levels and perspectives. [Di