Ulva-derived extracellular vesicles alleviate liver injury through a 7-hydroxycoumarin-associated EGFR-AKT regulatory axis.

Orally applicable strategies for liver injury remain limited, particularly when both efficacy and mechanistic clarity are required. Food-derived extracellular vesicles offer a promising approach, yet their complex composition often obscures the identification of active cargos and target pathways. Here, Ulva lactuca-derived extracellular vesicles (UEVs) were prepared using tangential flow filtration and evaluated in chemical liver injury models. UEVs retained measurable physicochemical characteristics under simulated gastrointestinal conditions and were internalized by hepatocytes. In CCl4-induced injury models, UEVs reduced oxidative damage, improved biochemical indicators of liver function, and attenuated early fibrotic responses. To explore the potential mechanism, untargeted metabolomics was integrated with network pharmacology to prioritize candidate cargos and signaling pathways. 7-Hydroxycoumarin (7-HC) was identified as a candidate component potentially associated with EGFR-related signaling. In TGF-β1-activated hepatic stellate cells, 7-HC reduced fibrotic activation and AKT phosphorylation in a pattern similar to that observed with pharmacological EGFR inhibition. These findings provide a practical approach for linking vesicle composition with biological activity and suggest that UEVs may act, in part, through a 7-HC-associated, AKT-sensitive signaling mechanism related to EGFR-associated pathways.