Technological Optimization and Antioxidant Efficacy via the NRF-2-Mediated Defense Pathway of Corylus avellana L. Skin Extracts: A Sustainable Approach for Developing Health-Promoting Natural Products

Background/Objectives: The valorization of bioactive compounds from food industry by-products aligns with sustainable development goals and represents a strategy for obtaining functional ingredients. Hazelnut (Corylus avellana L.) skins are a phenolic-rich residue with high antioxidant potential, but their extraction conditions and cellular mechanisms of action remain insufficiently explored. Methods: Ultrasound-assisted extraction was optimized using a 33 Full Factorial Design (FFD) by investigating temperature (30–50–70 °C), extraction time (1–2–3 h), and solvent composition (water/ethanol). Antioxidant activity was evaluated using multiple in vitro assays, including Total Phenolic Content (TPC), DPPH, ABTS, FRAP, and β-carotene bleaching (BCB) assays. The optimized extract (OE) was chemically characterized by UHPLC–MS/MS and its activity was evaluated in HepG2 cells for biocompatibility, modulation of intracellular ROS levels, and antioxidant pathway activation. Results: Optimal extraction conditions were identified as 30 °C, 70.86 min (1.181 h), and 21.13% ethanol (v/v), yielding an extract with enhanced antioxidant capacity. UHPLC–MS/MS analysis revealed 25 bioactive compounds, mainly flavonoids and phenolic acids, relevant for oxidative stress modulation. The extract significantly reduced tert-butyl hydroperoxide (TBH)-induced intracellular ROS levels, restoring antioxidant proteins involved in the Nuclear Factor erythroid 2-related factor 2 (NRF-2)-mediated defense pathway. Conclusions: The optimized hazelnut skin extract combines strong antioxidant efficacy with cellular compatibility, supporting its potential application as a functional ingredient for nutraceutical and pharmaceutical strategies targeting oxidative stress-related conditions.