Naringenin in Melanoma: Mechanistic Insights and Nanodelivery Strategies for Clinical Translation

Skin cancer, particularly melanoma, represents a major global health challenge primarily driven by ultraviolet (UV) radiation. Recent research highlights naringenin, a citrus-derived flavonoid, as a promising therapeutic candidate due to its ability to generate reactive oxygen species (ROS), induce cell cycle arrest, activate caspase-3, inhibit ERK1/2 and JNK MAPK signaling, and suppress angiogenesis. It also promotes melanogenesis by modulating Wnt/β-catenin and PI3K pathways and enhancing tyrosinase activity. Beyond its anticancer actions, naringenin exerts antioxidant, anti-inflammatory, and antiphotoaging effects, making it a versatile agent for dermatological applications. However, rapid metabolism, poor solubility, and limited bioavailability hinder its clinical translation. To overcome these challenges, advanced nanocarrier systems, including lipid nanoparticles, polymeric nanoparticles, liposomes, ethosomes, and nanostructured lipid carriers, have been engineered to enhance stability, skin penetration, and tumor-targeted delivery. These innovations highlight the potential of integrating mechanistic insights with delivery strategies to maximize therapeutic efficacy. Nonetheless, challenges such as high production costs, variability in phytochemical composition, and the need for harmonized manufacturing protocols remain. Addressing these barriers through multidisciplinary research and international collaboration is essential to translate phytochemical-based nanotherapies into safe and effective clinical options for melanoma management.