Phytochemistry and Biological Effects of the Juglans regia “Sorrento” Walnut Husk Extract on Human Keratinocyte Cells

Plants are a valuable source of natural compounds with diverse applications. Recently, increased attention has focused on waste products from the agricultural industry, including walnut husk. Given its potential as a sustainable source of bioactives, this work characterizes the alcoholic <i>Juglans regia</i> "<i>Sorrento</i>" walnut husk extract (WHE). The extract's phenolic content, antioxidant activity, and phytochemical composition were evaluated using spectrophotometry and UHPLC-HRMS-based untargeted metabolomics analysis. WHE exhibited a high total phenolic content (TPC = 1.45 ± 0.03 mg GAE/g dry extract) and a rich profile of phenolic acids, flavonoids, and tannins. Given this composition, WHE's biological activity was further tested in an in vitro human keratinocyte (HaCaT) model. At the concentration of 10 μg/mL, WHE showed no cytotoxicity and displayed significant antioxidant properties by modulating detoxifying proteins such as Nrf2. WHE also influenced mitochondrial metabolism, increased maximum respiration, preserved barrier integrity, and activated pathways for epithelial homeostasis. Overall, this study highlights the bioactivity of the <i>J. regia</i> "<i>Sorrento</i>" walnut husk extract. These findings support the valorization of walnut husk as a sustainable source of bioactives for dermatological and cosmetic products.