Objective To screen characteristic genes driving gastric mucosal “inflammation-cancer transformation” based on multi-omics data and Mendelian randomization (MR) causal inference methods, and to explore potential traditional Chinese medicine (TCM) intervention strategies. Methods Transcriptomic data and large-scale genetic data were integrated. Differential analysis, MR analysis, and protein-protein interaction network construction were performed to screen characteristic genes causally associated with gastric cancer risk. Subsequently, survival analysis, immune infiltration analysis, and immune mediation mechanism analysis were conducted on the identified genes. Finally, molecular docking-based virtual screening was performed on a TCM small-molecule compound library using core characteristic genes as targets to predict potential active components. Results A total of 30 continuously up-regulated differentially expressed genes were identified during the “inflammation-cancer transformation” process. MR analysis identified five core characteristic genes (S100A8, CXCR1, S100A9, S100A12, ZBED2) showing positive causal associations with gastric cancer risk. Among them, high expression of S100A12 was significantly associated with poor prognosis in patients, positively correlated with neutrophil infiltration, and negatively correlated with B-cell and CD4⁺ T-cell infiltration. Mediation analysis revealed that S100A12 may promote carcinogenic effects by negatively regulating CD25⁺CD4⁺ T cells (primarily regulatory T cells). Phenome-wide MR analysis suggested good potential safety for targeting S100A12. Virtual screening identified several TCM small-molecule compounds with high binding affinity to the S100A12 protein (e.g., C-curarine, physalin D). Conclusion S100A12 is a key characteristic gene linking chronic inflammation to gastric cancer development, driving “inflammation-cancer transformation” by reshaping the immune microenvironment. The screening of TCM small molecules targeting this gene provides lead compound candidates for intervening in gastric precancerous lesions. The established research framework integrating multi-omics and reverse drug screening offers a new approach for the precise prevention and drug development of gastric cancer.

gastric cancer  /  inflammation-cancer transformation  /  S100A12  /  immune infiltration  /  Mendelian randomization  /  C-curarine  /  physalin D