###### Abstract  
Melanin protects the skin against UV damage, whereas excessive melanin accumulation causes abnormal pigmentation and even melanoma. It has been reported that _Rosa rugosa_ exhibits antioxidant, anti-bacterial, anti-tumor, and anti-inflammation activities. The current study evaluated the melanogenesis-suppressing effect of \(R\). _rugosa_ extract and its solvent fractions (H\({}_{2}\)O, \(n\)-BuOH, 85% aq. MeOH, and \(n\)-hexane). The effect of \(R\). _rugosa_ on the extra/intra-cellular melanin and intra-cellular active tyrosinase levels, melanogenesis-related gene and protein expression, and PKA/CREB signaling pathway activation was investigated in \(\alpha\)-MSH-induced B16F10 cells. The results showed that \(R\). _rugosa_ effectively suppressed melanin secretion and tyrosinase activity at non-cytotoxic concentrations. \(R\). _rugosa_ extract down-regulated the melanogenesis-related expression of genes and proteins of tyrosinase, microphthalmia-associated transcription factor (MITF), tyrosinase-related protein (TRP)-1, and TRP-2. Furthermore, \(R\). _rugosa_ effectively inhibited the phosphorylation of the PKA/CREB proteins. Finally, the total polyphenol content of \(R\). _rugosa_ crude extract and its H\({}_{2}\)O, \(n\)-BuOH, 85% aq. MeOH, and \(n\)-hexane solvent fractions were 1383.9 \(\pm\) 44.5, 2004.7 \(\pm\) 43.4, 7270.3 \(\pm\) 54.5, 2064.1 \(\pm\) 34.8, and 1091.1 \(\pm\) 26.2 mg gallic acid equivalent/100 g extract, respectively. The anti-melanogenesis effect of \(R\). _rugosa_ was suggested to be exhibited by downregulating the PKA/CREB signaling pathway potentially due to a high content of polyphenols. Overall, \(R\). _rugosa_ crude extract and its solvent fractions could be considered sources of bioactive ingredients that can be used against hyperpigmentation. B16F10 melanoma cells; melanogenesis; PKA/CREB signaling pathway; _Rosa rugosa_; \(\alpha\)-MSH +
Footnote †: journal: _Sciences_  
down the process, the dopaquinone is further catalyzed to yield melanin in the presence of tyrosinase-related protein 1 (TRP-1) and TRP-2 [4]. The transcriptional regulation of the melanogenic genes and proteins such as tyrosinase and TRPs is mainly carried out by the microphthalmia-associated transcription factor (MITF) [5]. It has been reported that the cyclic adenosine monophosphate-dependent protein kinase A (PKA) and its downstream effector cyclic adenosine monophosphate response element-binding protein (CREB) are the main regulatory proteins in inducing melanogenesis [6]. Melanogenesis is influenced by several internal and external factors, namely, hormonal signaling, inflammatory cytokines, and UV irradiation. Although different mechanisms induce melanin synthesis, \(\alpha\)-melanocyte-stimulating hormone (\(\alpha\)-MSH) is one of the common downstream effectors and has been verified to stimulate melanin secretion in the presence of several stimuli [7]. Under the stimulation of \(\alpha\)-MSH, the increased intracellular cAMP levels subsequently activate the cAMP-dependent protein kinase (PKA) via phosphorylation [8]. Next, the phosphorylated PKA activates CREB, which then causes an increased level of MITF transcription. Overexpression MITF further stimulates the production of tyrosinase, TRP-1, and TRP-2 [9]. Excessive melanogenesis-induced pigmentation and pigmentary disorders have been focused on continually, and tyrosinase inhibitors have been widely studied as anti-melanogenic therapeutics all over the world [10]. Several chemical regents have been verified to possess anti-melanogenesis effects [11]. However, long-term use of these regents causes serious side effects including inflammation, cytotoxicity, skin irritation, and itchiness [12]. Therefore, finding and developing natural, safe, and effective whitening agents from natural sources is essential. _Rosa rugosa_, also called Japanese or rugosa rose, is a plant originally from Asia [13]. Previous studies reported that _R. rugosa_ exhibits antioxidant, anti-bacterial, anti-tumor, and anti-inflammation activities [14; 15; 16].