White Grape Skin Extraction, Analytical Profile, and Biological Activity: From the Laboratory to the Industrial Scale Within a Circular Economy Framework

Background: The sustainable use of agro-industrial by-products is essential to reduce environmental impact and enhance resource efficiency. In this study, white grape skins (WGSs), a distillation by-product of grappa production, are valorized through the development of an eco-friendly extraction process. Methods: At the laboratory scale, water-based and hydroalcoholic extractions are evaluated, prioritizing the water-based method due to its better scalability and eco-sustainability. Furthermore, this green extraction method enables industrial scale-up by Distillerie Bonollo Umberto S.p.A. (Mestrino, Italy), resulting in Vituva®, an industrial extract with a composition comparable to its water-based laboratory counterpart. LC-HRMS-based targeted metabolomics identified 50 metabolites in the hydroalcoholic extract, 36 in the waterbased extract, and 37 in the industrial extract, which included mainly polyphenols such as flavonoids and phenolic acids. Results: In vitro assays show that the water-based and industrial extracts exhibit significant anti-inflammatory activity, especially in gastric epithelial cells, while the hydroalcoholic extract displays stronger antioxidant activity via Nrf2 pathway activation but was more cytotoxic, possibly due to polyphenol-induced hormesis. Notably, the industrial extract also activates Nrf2 to a lesser extent, supporting its dual bioactivity profile. Chemoinformatic and statistical analyses support the identification of the likely mechanisms of action. Conclusions: Overall, this work demonstrates how green chemistry and circular economy principles transform a waste product into a high-value bioactive ingredient.