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Diabetes mellitus-induced erectile dysfunction (DMED) remains a challenging condition without effective targeted therapies. This study aimed to explore the potential mechanisms and molecular targets of Radix Paeoniae Rubra and Radix Angelicae Sinensis Granules (RAG) in DMED using a combination of network pharmacology and experimental validation. Active compounds of RAG and their predicted targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP). DMED-related genes were collected from GeneCards, OMIM, and PharmGKB. Shared targets were identified and used to construct protein-protein interaction networks. A drug–ingredient–disease–target network was established using Cytoscape, and functional enrichment analyses (GO and KEGG) were performed via OmicShare. Molecular docking was carried out with Molecular Operating Environment (MOE) software to assess compound–target interactions. Finally, the therapeutic effects of RAG were evaluated in DMED rat models.
Twenty bioactive constituents and 25 overlapping targets were identified, implicating pathways associated with vasodilation, apoptosis, protein secretion, and hypoxia. Enriched pathways included HIF-1, MAPK, cAMP, and Ras signaling. Six hub genes—INS, CAT, BDNF, CASP3, CRP, and HMOX1—were predicted as primary targets of RAG. Docking studies showed strong binding affinities of oleic acid, catechin, and butylated hydroxytoluene to these targets. In vivo, RAG administration improved penile hemodynamics, enhanced nitric oxide production, ameliorated histopathological changes, upregulated eNOS, iNOS, and HMOX1, and downregulated HIF-1 expression. The findings suggest that RAG may exert protective effects against DMED through modulation of the HIF-1α/HMOX1 pathway. This study provides mechanistic insights supporting the potential use of RAG as a therapeutic strategy for DMED.
