Network Toxicology Predicts the Novel Synergistic Roles of MDM2 and CYP3A4 in Ergotamine-Induced Peripheral Gangrene

Objective Ergotamine, a natural toxic molecule retained by Claviceps spp. through long-term evolution. This study aimed to explore the multi-target synergistic mechanism of ergotamine-induced peripheral gangrene based on network toxicology, so as to reveal the elaborate systemic toxicological design of natural toxicants. Method Network toxicology approaches were employed, including target prediction, protein-protein interaction (PPI) network construction, Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, to screen the key core genes of ergotamine action. Molecular docking was performed to verify the binding ability between ergotamine and core proteins. First, a comprehensive analysis of ergot toxicity was conducted to construct a toxic action network including peripheral gangrene; on this basis, the toxic endpoint of peripheral gangrene was focused on to construct its specific action network. Result Network toxicology analysis confirmed that ergotamine mediates neurological and vasoconstrictive effects via 5‑hydroxytryptamine, dopamine, and adrenergic receptors, consistent with known mechanisms. With peripheral gangrene as the key endpoint, nine core genes (F2, F10, REN, PLAU, CYP3A4, IL-2, STAT1, JAK2, and MDM2) were identified as critical regulators. Molecular docking revealed strong interactions between ergotamine and F2, CYP3A4, PLAU, REN, and MDM2. Mechanistically, ergotamine simultaneously promotes thrombosis (via F2), exacerbates vasoconstriction (via REN), impairs fibrinolysis (via PLAU), sustains toxicity by reducing metabolic clearance (via CYP3A4), and disrupts cell cycle repair (via MDM2). These targets act synergistically to drive the onset and progression of peripheral gangrene. Conclusion Ergotamine forms a complementary toxic regulatory network by targeting multiple systems, reflecting nature’s elaborate multi-target synergistic design. Caution is warranted for p53-MDM2 anti-tumor inhibitors combined with ergotamine or CYP3A4 inhibitors.