Exploring the Mechanism of Luteolin in Managing Comorbid Diabetes Mellitus and Pulmonary Hypertension based on Integrated Computational Strategies

Background: Diabetes Mellitus (DM) is a common comorbidity in patients with Pulmonary Hypertension (PH), and PH may represent a novel vascular complication of DM. Luteolin, a natural flavonoid widely found in herbs such as honeysuckle and foods such as celery, has shown therapeutic effects on both DM and PH, though its mechanisms remain unclear. Objective: This study aimed to elucidate the molecular mechanisms of luteolin in treating DM and PH comorbidity (DM/PH) using network pharmacology, molecular docking, and molecular dynamics simulations. Methods: The targets of luteolin were identified from multiple databases, and disease-related genes for DM and PH were collected from OMIM, DisGeNET, GeneCards, CTD, DrugBank, TTD, NCBI, SymMap, and GEO. Genes appearing in at least two databases were considered potential target genes. Common targets were visualized with a Venn diagram. GO and KEGG enrichment analyses were performed via Database for Annotation, Visualization, and Integrated Discovery (DAVID). Protein-Protein Interaction (PPI) and drug-target-pathway networks were constructed using Cytoscape. Core targets were identified and verified through molecular docking using AutoDockTools, followed by molecular dynamics simulations with Gromacs. Results: A total of 166 potential therapeutic targets were identified. Enriched biological processes included transcription regulation, apoptosis, protein phosphorylation, and inflammatory response. Key pathways involved PI3K-Akt, HIF-1, IL-17 signaling, and lipid metabolism. Core targets included TP53, Stat3, AKT1, EGFR, TNF, IL6, HSP90AA1, JUN, HIF1A, and SRC. Molecular docking revealed a strong binding affinity between luteolin and the core targets EGFR and SRC, with further validation provided by molecular dynamics simulations, which confirmed stable binding (free energies: -31.54 and -36.75 kJ/mol). Conclusion: Luteolin may exert therapeutic effects on DM/PH by interacting with multiple targets and signaling pathways, offering theoretical support for future basic and clinical research.