Multi-Target Mechanisms of Celery-Derived Luteolin Glycosides Revealed by Network Pharmacology: A Systems-Level Perspective on Therapeutic Targeting of Inflammation and Oxidative Stress

Andzely Zahana Putri (Sekolah Tinggi Ilmu Kesehatan Harapan Ibu Jambi)
Indri Meirista (Sekolah Tinggi Ilmu Kesehatan Harapan Ibu Jambi)
Hendri Satria Kamal Uyun (sekolah tinggi ilmu farmasi padang)
Rizky Yulion Putra (Sekolah Tinggi Ilmu Kesehatan Harapan Ibu Jambi)

Journal of Natural Products and Drug Development
Vol. 1 No. 1 (2025): Journal of Natural Products and Drug Development

Background of study: Luteolin and its glycoside derivatives from natural sources possess potent anti-inflammatory and antioxidant properties, yet their multi-target mechanisms remain incompletely characterized.Aims and scope of paper: This study aimed to systematically elucidate the multi-target pharmacological mechanisms of three luteolin glycoside compounds (Luteolin 7-apiosyl(1→6)glucoside, Luteolin 7-sambubioside, and Luteolin 7-primeveroside) extracted via NaDES technology using integrated network pharmacology approaches, focusing on identification of core therapeutic targets and pathways modulating inflammatory and oxidative stress responses.Method: Comprehensive network pharmacology analysis was conducted through: (1) target prediction via TargetNet and Swiss Target Prediction platforms; (2) protein-protein interaction (PPI) network construction using STRING database; (3) disease-associated gene identification through GeneCards; (4) topological centrality analysis using Cytoscape with CytoNCA plugin. Hub proteins were prioritized based on degree, betweenness, and closeness centrality measures.Result: Network analysis identified 40 predicted targets with 5-6 intersection genes per compound. Venn diagram analysis revealed TNF (Tumor Necrosis Factor-alpha) as the critical hub protein (degree centrality 3.0, betweenness centrality 7.0), establishing a TNF-XDH-CYP1A2-ALOX15 integrated regulatory axis. Luteolin 7-apiosyl(1→6)glucoside and Luteolin 7-primeveroside demonstrated highest potency with 6 intersection targets, while Luteolin 7-sambubioside exhibited selective oxidative stress pathway.Conclusion: Network pharmacology analysis successfully elucidated the integrated TNF-XDH-CYP1A2-ALOX15 axis as a core mechanism through which luteolin glycosides coordinately modulate inflammatory and oxidative stress pathways. These findings provide mechanistic validation for therapeutic potential in chronic inflammatory diseases including inflammatory bowel disease, type 2 diabetes, and cardiovascular disorders. Future experimental validation is essential to translate these predictions into clinical therapeutic applications.