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Endothelin-1 (ET-1) plays an indispensable role in epidermalpigmentation in hyperpigmentary disorders due to a centralrole in melanogenesis. Nevertheless, precise mechanism involvedin ET-1-induced hyperpigmentation is still undefined.Glycoprotein (transmembrane) non-metastatic melanoma proteinb (GPNMB) is a key element in melanosome formation.Therefore, we speculated that GPNMB was correlated withET-1-induced pigmentation. After culturing with ET-1, melaninsynthesis was significantly up-regulated, accompanying withincreased expression of GPNMB and microphthalmia- associatedtranscription factor (MITF). Total number of melanosomesand melanin synthesis were sharply reduced viaGPNMB-siRNA transfection, indicating ET-1-induced pigmentationby GPNMB-dependent manner. Furthermore, MITFsiRNAtransfection strikingly inhibited GPNMB expression andthe melanogenesis, and this suppression failed to be alleviatedby ET-1 stimulation. All of these results demonstrated that ET-1can trigger melanogenesis via the MITF-regulated GPNMBpathway. Taken together, these findings will provide a new explanationof how ET-1 induces hyperpigmentation, and possiblysupply a new strategy for cosmetic studies. [BMB Reports2013; 46(7): 364-369]