Objective  To comprehensively investigate the potential molecular mechanisms of the Chinese herb Paeonia Radix Rubra in treating endometrial carcinoma, and to provide a scientific basis for its clinical application.

Methods  Active ingredients and corresponding targets of Paeonia Radix Rubra were predicted using Traditional Chinese Medicine Systems Platform (TCMSP), The Encyclopedia of Traditional Chinese Medicine 2.0 (ETCM2.0), Traditional Chinese Medicine In-formation Database (TCM-ID), PubChem and SwissTargetPrediction. Endometrial carcinoma-related targets were retrieved from GeneCards, Digsee and differentially expressed genes from the Gene Expression Omnibus (GEO) database, followed by screening of key module genes via weighted gene co-expression network analysis (WGCNA). Intersecting targets were obtained after intersection analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID database, and an “ingredient-target” network was constructed to identify core ingredients. Mendelian randomization analysis was adopted to screen core targets associated with endometrial carcinoma. Single-cell sequencing data were used to clarify the cellular distribution of these targets. Finally, molecular docking and molecular dynamics simulations were conducted to verify their binding stability.

Results  A total of 23 active ingredients of Paeonia Radix Rubra and 324 potential drug targets were identified, and 39 intersecting targets were obtained after intersection analysis. Network topological analysis of the “Paeonia Radix Rubra-ingredient-intersecting target” network revealed that baicalein, albiflorin and ellagic acid were the core ingredients. Mendelian randomization analysis demonstrated that breast cancer resistance protein (ABCG2), insulin receptor (INSR), and protein kinase C beta (PRKCB) were the core therapeutic targets of ingredientPaeonia Radix Rubra against endometrial carcinoma. Subsequent GO and KEGG enrichment analyses of core targets indicated that their underlying mechanisms were associated with cancer-related signaling pathways, including the hypoxia-inducible factor-1 (HIF-1), mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling pathways. Single-cell sequencing revealed that these core targets were mainly enriched in tumor endothelial cells. Molecular docking and molecular dynamics simulations verified the stable binding capacity between active ingredients of Paeonia Radix Rubra and core targets.

Conclusion  ABCG2, INSR and PRKCB are the core targets of Paeonia Radix Rubra against endometrial carcinoma. They exhibit significant causal associations with the risk of endometrial carcinoma and are highly expressed in tumor epithelial cells and tumor-associated fibroblasts. Paeonia Radix Rubra may synergistically regulate signaling pathways such as the PI3K/Akt pathway via multiple active ingredients, acting on core targets to inhibit proliferation and induce apoptosis of endometrial carcinoma cells, and exert therapeutic effects by modulating the functions of epithelial cells and fibroblasts in the tumor microenvironment.

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