Extracellular Vesicles from Capparis spinosa Modulate Epithelial-to-Mesenchymal Transition in Huh7 Hepatocellular...

Background: Epithelial-to-mesenchymal transition (EMT) is a cellular reprogramming process characterized by coordinated changes in signaling, membrane organization and metabolism. In a previously established and deeply characterized Huh7 EMT model, it was demonstrated that TGF-β stimulation induces a reproducible shift toward a mesenchymal state accompanied by lipidomic and metabolic remodeling. Building on this framework, the present study evaluates whether extracellular vesicles (EVs)-enriched fractions derived from Capparis spinosa can modulate these EMT-associated alterations. Methods: After detailed physicochemical, molecular, lipidomic and metabolomic characterization, C. spinosa EVs were applied to EMT-induced Huh7 cells. The vesicles were efficiently internalized and, while not inducing a complete epithelial reversion, they attenuated mesenchymal features, indicating a modulatory rather than inhibitory action. Results: Lipidomic profiling showed a partial correction of TGF-β-induced changes including diacylglycerols, phosphoinositides and triglycerides, suggesting interference with lipid signaling and membrane turnover. Metabolomic data further points to reduced mitochondrial and fatty acid oxidation stress, reflected in the re-equilibration of carnitine and acylcarnitine species. Conclusions: Together, these findings indicate that C. spinosa EVs are able to attenuate EMT-associated metabolic and membrane remodeling, positioning them as promising modulators of tumor cell plasticity.