Origin-specific metabolomic profiling and network pharmacology propose potential multi-target antioxidant mechanisms...

Black Sesame Seeds (BSS) are consumed as an edible herbal food with medicinal food homology and possess potent antioxidant properties; however, their metabolic compositions and corresponding antioxidant efficacies substantially vary across different geographical origins. This study investigates the underlying multi-component and multi-target antioxidant mechanisms of BSS from various geographical origins. An integrated computational and experimental approach combining UHPLC-Q-Exactive Orbitrap MS/MS-based metabolomics, network pharmacology, and molecular docking was employed. Metabolomic profiling identified a diverse array of active phytochemicals enriched in BSS, including lipophilic lignans (e.g., (+)-eudesmin), vitamin E derivatives (e.g., γ-tocotrienol), and hydrophilic flavonoids (e.g., quercetin). Subsequent network and structural biology analyses revealed that these diverse compounds exert complementary multi-target effects to mitigate oxidative stress by targeting core hub proteins, particularly AKT1 and TP53. Specifically, molecular docking demonstrated that lipophilic components exhibit strong binding affinities to the hydrophobic cavities of AKT1, whereas hydrophilic polyphenols establish robust hydrogen-bonding networks with TP53. Pathway enrichment analyses further suggested that BSS exerts its profound cytoprotective effects primarily by modulating the PI3K-Akt and apoptosis signaling cascades, thereby restoring intracellular redox homeostasis. In conclusion, this study systematically predicts the complex structural and pharmacological basis of BSS against oxidative damage, laying a solid theoretical hypothesis for the future development of BSS-derived natural antioxidants and functional therapeutics.