Citrulluside T, Isolated from the Citrullus lanatus Stem, Inhibits Melanogenesis in α-MSH-Induced Mouse B16F10 Cells

With the increasing number of cosmetic consumers emphasizing value consumption and sustainability, upcycling has gained attention as a solution to agricultural by-products, which are the main culprits of environmental problems. In this study, we isolated citrulluside T with whitening activity from discarded Citrullus lanatus stems and investigated the anti-melanogenic effect of citrulluside T and the underlying mechanisms. We found that citrulluside T did not exhibit cytotoxicity up to a concentration of 90 μM and significantly reduced the melanin content and intracellular tyrosinase activity in B16F10 cells. In addition, citrulluside T inhibited the expression of melanogenic enzymes such as tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2, as well as melanin synthesis via cAMP-dependent protein kinase (PKA)/cAMP response element-binding protein (CREB)-mediated downregulation of microphthalmia-associated transcription factor (MITF), a key transcription factor in melanogenesis. Furthermore, we found that citrulluside T exerted its anti-melanogenic effect by downregulating the β-catenin protein and upregulating phosphorylated β-catenin. Finally, we confirmed that citrulluside T was safe for skin through skin irritation tests on 33 subjects, suggesting its applicability as a protective agent against hyperpigmentation for topical applications such as cosmetics and ointments.