Plant species are a reservoir of natural compounds that can potentially be used to treat different diseases. Citrus medica Linn. belonging to the Rutaceae family, has been used for centuries in medicine for its antioxidant, anti-inflammatory, antimicrobial, antiviral, and antihyperglycemic properties. These activities are ascribable not only to the presence of health-promoting macronutrients and micronutrients, such as carbohydrates, minerals, amino acids, and vitamins, but also to specialized metabolites, such as flavonoids (apigenin, hesperetin, hesperidin, naringin, naringenin, rutin, quercetin, and diosmin), coumarins (citropten, scoparone, and bergapten), terpenes (limonene, γ-terpinene, limonin, and nomilin), and phenolic acids (p-coumaric acid, trans-ferulic acid, and chlorogenic acid). In recent years, particular attention has been focused on the antioxidant, anti-inflammatory, antimicrobial activity, antidiabetic, anticancer, and neuroprotective activity of C. medica. However, although many studies have reported this species’ chemical and biological properties, the literature has never been analyzed via a systematic approach. For this reason, using PubMed and Scopus as databases, we performed a systematic review of C. medica’s chemical composition and biological properties to inspire new research approaches and increase its curative application.

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.