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The peripheral benzodiazepine receptor (TSPO/PBR) is highly conserved among different species but with perplexing biochemical functions. Multiple ligands of TSPO show commendable regulatory activities in lots of biological functions, such as neuro-protection, cholesterol transport, and so on. These researches support that TSPO may be a potential target for disease treatment and drug development. Previous studies have shown that its ligands benzodiazepines show a satisfactory effect on melanogenic promotion. However, the potential application of TSPO in drug development for pigmentary disorder needs further investigation. In this study, we confirmed the melanogenesis induction of TSPO ligand, Ro5-4864 in mouse melanoma cell lines, human skin tissue, and zebrafish embryos by inducing melanin synthesis and melanosome transport. Molecular genetics and pharmacological studies showed that TSPO deficiency did not affect melanin production in B16F10 cells and zebrafish embryos, nor did it affect the melanin promotion effect of Ro5-4864. Whether or not TSPO exists, the expression of lots of melanogenesis-related proteins, such as TYR, TRP-1, DCT, Mlph, and Rab27 was upregulated with the Ro5-4864 administration. These results indicated that Ro5-4864 induces melanogenesis in a TSPO-independent manner, which is inconsistent with previous research. This research is a reminder that we need to be very careful during target validation in drug development. [ABSTRACT FROM AUTHOR]