The Anti-Cancer Potential of Genistein: Single-Cell RNA Sequencing Analysis and Spatial Transcriptome Reveal That Genistein Targets HSD17B1 to Inhibit the Progression of Gastric Adenocarcinoma

Genistein has anti-cancer effects, but its molecular targets in gastric adenocarcinoma (GA) are unclear. This study used single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to explore genistein's "drug-gene-cell" interactions in GA. GA- and genistein-related target genes were retrieved and intersected with differentially expressed genes identified from bulk transcriptomic data. Machine learning screened candidates, and survival analysis assessed prognosis. Molecular docking with genistein validated key genes, with molecular dynamics assessing binding stability. <i>HSD17B1</i>, <i>EZH2</i>, <i>CCNB1</i>, <i>CCNB2</i>, <i>CDKN2A</i>, and <i>IGFBP6</i> were identified as key candidate genes with prognostic value for GA. Specifically, samples in the <i>IGFBP6</i> high-expression group were associated with higher survival probability, whereas the opposite trend was observed for the other five genes. In addition, HSD17B1 was genistein's main target in GA treatment, showing a strong binding affinity with genistein (binding energy of -8.1 kcal/mol). scRNA-seq analysis indicated that <i>HSD17B1</i> was predominantly expressed in epithelial cells and was significantly involved during their malignant transformation (confirmed by ST). This study identified <i>HSD17B1</i> as a critical target gene for genistein in GA treatment, emphasizing its roles in the malignant transformation of epithelial cells, thus providing a theoretical foundation for understanding the therapeutic mechanism of genistein in GA.