Abstract

Uralsaponin X is a novel HMGB1 inhibitor derived from licorice. • Uralsaponin X inhibits HMGB1-induced melanocyte dendrite and melanosome transfer. • Uralsaponin X and glabridin were co-encapsulated into lipid nanoparticle. • This co-delivery approach synergizes the anti-hyperpigmentary efficacy. Hyperpigmentation is a common skin disorder that affects millions of people worldwide. The growing demand for ameliorating undesirable hyperpigmentary disorders has driven the development of novel intervention strategies. Herein, we identified uralsaponin X, a licorice-derived high-mobility group box 1 (HMGB1) inhibitor, which exerts potent anti-melanogenic effects in zebrafish larval models. Cell culture experiments demonstrated that uralsaponin X did not alter melanin biosynthesis in melanocytes but specifically inhibited HMGB1-mediated melanocyte dendrite extension and melanosome transport to the plasma membrane, thereby reducing the transfer of melanosomes to keratinocytes. Furthermore, we developed a nanoscale co-delivery system to co-encapsulate uralsaponin X and glabridin, a well-known tyrosinase inhibitor, into lipid nanoparticles to enhance skin penetration and achieve a synergistic depigmenting effect. The uralsaponin X- and glabridin-loaded lipid nanoparticle (UG-LNP) effectively improved cellular internalization and skin permeability. In a UVB-triggered hyperpigmentation guinea pig model, UG-LNP demonstrated remarkable depigmenting capacity by suppressing melanin synthesis, melanosome transfer, and inflammatory cell infiltration. Compared with glabridin monotherapy, UG-LNP achieved better in vivo therapeutic outcomes, as demonstrated by the alleviation of UVB-induced epidermal thickening and melanin granule accumulation in the epidermis. Collectively, this study identified uralsaponin X as a novel HMGB1 inhibitor possessing potent anti-hyperpigmentation properties. Furthermore, lipid nanoparticle-based co-delivery of glabridin and uralsaponin X represents a