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    Advanced glycation end products promote melanogenesis via activating NLRP3 inflammasome in human dermal fibroblasts. The Journal of investigative dermatology Advanced glycation end products (AGEs) accumulation is significantly increased in the dermis of photoaged skin and plays crucial roles in photoaging. Although AGEs have been found to contribute to the yellowish discoloration of photoaged skin, their roles in photoaging-associated hyperpigmentation disorders have not been extensively studied. In this study, we observed that AGEs, NLRP3 and IL-18 were increased in the dermis of sun-exposed skin and lesions of melasma and solar lentigo and that dermal deposition of AGEs was positively correlated with epidermal melanin levels. Additionally, we found AGEs-BSA potently activated NLRP3 inflammasome and promoted IL-18 production and secretion in cultured fibroblasts, which was mediated by RAGE/NF-κB pathway. Moreover, AGEs-BSA significantly promoted melanogenesis through increasing tyrosinase activity and expression of microphthalmia-associated transcription factor and tyrosinase, which was dependent on NLRP3 inflammasome activation and IL-18 secretion in fibroblasts. Notably, AGEs-collagen could activate NLRP3 inflammasome in fibroblasts and enhance melanogenesis. Further, we found IL-18 enhanced melanogenesis through binding to its receptor and activating p38 MAPK and ERK1/2 signaling pathways in melanocytes. Importantly, the pro-melanogenesis of AGEs-BSA was verified in ex vivo cultured skin and mice models. These findings suggest that dermal AGEs stimulate melanogenesis and contribute to the development of photoaging-associated hyperpigmentation disorders. 10.1016/j.jid.2022.03.025
    Ablation of H/glucose Exporter SLC45A2 Enhances Melanosomal Glycolysis to Inhibit Melanin Biosynthesis and Promote Melanoma Metastasis. The Journal of investigative dermatology Mutations in SLC45A2 are responsible for oculocutaneous albinism type 4 in many species and associated with melanoma susceptibility, but the molecular mechanism is unclear. Here, we used Slc45a2-deficient melanocyte and mouse models to elucidate the roles of Slc45a2 in melanogenesis and melanoma metastasis. We find that the acidified cellular environment impairs the activity of key melanogenic enzyme tyrosinase in Slc45a2-deficient melanocytes. Slc45a2 is identified as a proton/glucose exporter in melanosomes, and its ablation increases acidification of melanosomal pH through enhanced glycolysis. Intriguingly, C-glucose labeled metabolic flux and biochemical assays show that melanosomes are active glucose-metabolizing organelles, indicating that elevated glycolysis mainly occurs in melanosomes due to Slc45a2-deficiency. Moreover, Slc45a2-deficiency significantly up-regulates the activities of glycolytic enzymes and PI3K/Akt signaling to promote glycolysis-dependent survival and metastasis of melanoma cells. Collectively, our study reveals that the H/glucose exporter Slc45a2 mediates melanin synthesis and melanoma metastasis primarily via modulating melanosomal glucose metabolism. 10.1016/j.jid.2022.04.008