Using Network Pharmacology and in vivo Experiments to Uncover the Mechanisms of Radix Paeoniae Rubra and Radix Angelicae Sinensis Granules in Treating Diabetes Mellitus-Induced Erectile Dysfunction

Jie Wang,1,* Yingxue Guo,2,* Jie Huang,2 Junfeng Yan,1 Jianxiong Ma3,4 1Zhejiang Hospital, Hangzhou, Zhejiang, 310000, People’s Republic of China; 2Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China; 3The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, People’s Republic of China; 4The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianxiong Ma, Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, People’s Republic of China, Email [email protected] Junfeng Yan, Department of Urology, Zhejiang Hospital, Hangzhou, Zhejiang, 310000, People’s Republic of China, Email [email protected]: Diabetes mellitus-induced erectile dysfunction (DMED) lacks targeted therapies. This study investigates the mechanisms and targets of Radix Paeoniae Rubra and Radix Angelicae Sinensis Granules (RAG) in treating DMED using network pharmacology and animal models.Methods: We identified RAG’s active ingredients and potential targets from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. DMED targets were obtained from GeneCards, OMIM, and PharmGKB. Common targets were identified using R, and interaction networks were built. Cytoscape was used to construct a drug-ingredient-disease-target network, and OmicShare tools performed Gene Ontology and KEGG pathway analyses. Molecular Operating Environment software assessed compound-core gene interactions. Additionally, animal models were used for validation.Results: Twenty compounds and 25 common targets linked to vasodilation, protein secretion, apoptosis, and hypoxia were selected. Key pathways included HIF-1, MAPK, cAMP, and Ras. Six core genes (INS, CAT, BDNF, CASP3, CRP, HMOX1) were targeted by RAG. Molecular docking showed stable interactions with oleic acid, catechin, and butylated hydroxytoluene. RAG increased NO, intracavernous pressure, and improved penile histology in rats, upregulating eNOS, iNOS, HMOX1, and downregulating HIF-1.Conclusion: RAG may treat DMED via the HIF-1α/HMOX1 pathway, offering a potential novel therapy for DMED.Keywords: Radix Paeoniae Rubra, Radix Angelicae Sinensis, diabetes mellitus, erectile dysfunction, network pharmacology, hub genes, HIF-1 pathway