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Article

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

1
The School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
2
Biological Science Research Center, Southwest University, Chongqing 400715, China
3
The State Key Laboratory of Resource Insects, Southwest University, Chongqing 400715, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(21), 10369; https://doi.org/10.3390/ijms262110369
Submission received: 26 August 2025 / Revised: 15 October 2025 / Accepted: 23 October 2025 / Published: 24 October 2025
(This article belongs to the Section Molecular Oncology)

Abstract

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. HSD17B1, EZH2, CCNB1, CCNB2, CDKN2A, and IGFBP6 were identified as key candidate genes with prognostic value for GA. Specifically, samples in the IGFBP6 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 HSD17B1 was predominantly expressed in epithelial cells and was significantly involved during their malignant transformation (confirmed by ST). This study identified HSD17B1 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.
Keywords: gastric adenocarcinoma; genistein; single-cell RNA sequencing analysis; molecular docking; spatial transcriptome gastric adenocarcinoma; genistein; single-cell RNA sequencing analysis; molecular docking; spatial transcriptome

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MDPI and ACS Style

Wang, X.; Zhang, J.; Jiang, J.; Wang, Y. 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. Int. J. Mol. Sci. 2025, 26, 10369. https://doi.org/10.3390/ijms262110369

AMA Style

Wang X, Zhang J, Jiang J, Wang Y. 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. International Journal of Molecular Sciences. 2025; 26(21):10369. https://doi.org/10.3390/ijms262110369

Chicago/Turabian Style

Wang, Xianbing, Junyuan Zhang, Jiaying Jiang, and Yi Wang. 2025. "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" International Journal of Molecular Sciences 26, no. 21: 10369. https://doi.org/10.3390/ijms262110369

APA Style

Wang, X., Zhang, J., Jiang, J., & Wang, Y. (2025). 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. International Journal of Molecular Sciences, 26(21), 10369. https://doi.org/10.3390/ijms262110369

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