Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin 2228-5881 16 1 2026 05 19 Apigenin as a Multi-Targeted Agent in Gastrointestinal Cancers: A Systems Pharmacology Approach 74 90 10.34172/apb.025.45970 EN Duaa Kamel Al-Moussawi Aseel Kamil Mohammed Al-mosawi Awatif Mokar Dayesh Mohammad Hosseinzadeh Hesari https://orcid.org/0000-0002-9910-9385 Hamid Cheshomi https://orcid.org/0000-0001-7925-7797 Journal Article 10.34172/apb.025.45970 2025 06 30 2025 09 25 Introduction: Apigenin, a dietary flavonoid found in various medicinal plants, has demonstrated notable anticancer effects. However, its multi-targeted molecular mechanisms in gastrointestinal (GI) cancers remain poorly understood. This study aimed to comprehensively identify the key molecular targets and signaling pathways influenced by apigenin in five major GI cancers: esophageal, gastric, colorectal, pancreatic, and liver cancers. Methods: Natural plant sources of apigenin were identified, and apigenin-related genes were extracted from public databases and scientific literature. Protein–protein interaction (PPI) networks were constructed, followed by hub gene identification using CytoHubba software. Functional enrichment analyses, survival analysis, and gene expression profiling were conducted using the STRING, DAVID, and GEPIA platforms. Molecular docking was performed to evaluate the binding affinities between apigenin and key oncogenic proteins. Results: Hub genes, including TP53, AKT1, STAT3, BCL2, and HIF1A, were identified as central nodes in PPI network. Expression and survival analyses revealed that HIF1A, IL6, and STAT3 were significantly upregulated in tumors and correlated with poorer prognosis. Enrichment analyses indicated that apigenin-responsive targets were significantly involved in the PI3K-Akt, MAPK, JAK-STAT, and mTOR signaling pathways. Docking studies confirmed the high binding affinity of apigenin to key targets, such as AKT1 and PTEN. Conclusion: The results suggest that apigenin exerts its anticancer effects by modulating multiple oncogenic pathways and interacting with key regulatory proteins involved in tumor progression and survival. This integrative systems pharmacology study provides suggestive evidence for the pleiotropic anticancer potential of apigenin in GI cancers and supports its development as a multi-target agent in precision oncology.