In Silico Exploration of the Angiogenic Potential of Theophylline as a Drug Repurposing Candidate through Network Pharmacology

Theodorus Rexa Handoyo (Universitas 17 Agustus 1945 Jakarta)
Cherry Vanesa (Universitas 17 Agustus 1945 Jakarta)

Indonesia Natural Research Pharmaceutical Journal (INRPJ)
Vol 11, No 1 (2026)

Theophylline is a methylxanthine drug that has been widely used in the management of respiratory disorders, particularly asthma and chronic obstructive pulmonary disease. In addition to its bronchodilator activity, theophylline exhibits a broad pharmacological profile, suggesting that it may possess biological activities beyond its conventional therapeutic applications. This study aimed to explore the potential of theophylline as a drug repurposing candidate associated with angiogenesis using a network pharmacology approach. Potential molecular targets of theophylline were obtained from SwissTargetPrediction, while angiogenesis-associated genes were retrieved from GeneCards using a Relevance Score threshold of >50. Overlapping genes between the two datasets were subsequently analyzed using protein-protein interaction (PPI) analysis, Cytoscape, and CytoHubba with the Maximal Clique Centrality (MCC) method. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify the biological functions and signaling pathways associated with the overlapping targets. Six overlapping targets were identified, namely KDR, EPHB4, SRC, TYMP, JAK2, and PDE3B. PPI analysis demonstrated that EPHB4, SRC, KDR, JAK2, and PDE3B formed a connected interaction network, while SRC and JAK2 showed the highest MCC rankings. GO analysis indicated associations with protein tyrosine kinase activity, transmembrane receptor protein tyrosine kinase activity, vascular endothelial growth factor receptor activity, and regulation of PI3K/AKT signaling. KEGG analysis identified the VEGF signaling pathway among the enriched pathways. Overall, these findings indicate a potential molecular association between theophylline and angiogenesis-related mechanisms, supporting further investigation of theophylline as a drug repurposing candidate. However, this study is entirely computational and should be considered hypothesis-generating rather than evidence of angiogenic activity or therapeutic efficacy. Further in vitro and in vivo studies are required to validate the identified molecular associations and biological mechanisms.