Melanin Biosynthesis Research Articles

Potential of Herbal Extracts as Sunscreens and Antihyperpigmentation Treatment

Background: Skin pigmentation is one of the most serious problems in the adult population of all races. The underlying factors of skin pigmentation are excessive exposure to UV radiation, oxidative stress, and other provocative causes that cause melasma, black spots, and post-inflammatory hyperpigmentation. Hence, treating hyperpigmentation disorders is challenging. Objective: Skin pigmentation occurs as a process of melanin biosynthesis triggered by UV exposure. Tyrosinase, an enzyme that catalyzes the rate-confining step in melanogenesis, if inhibited, can cause skin hypopigmentation. This has evoked an interest in reviewing plant extracts/ phytoconstituents, which can serve the purpose of sun protection and treat hyperpigmentation, ensuring skin glow for a better quality of life. Methods: A literature search on Medline, PubMed, Embase, and Scopus databases was done using various keywords like hyperpigmentation, melasma, skin-lightening agents, and sunscreen. Results: Sun protection products for canopy with photo-aging and skin pigmentation are recommended. Tyrosinase inhibitors are first-line topical medicines available as single or combined topical formulations. Hydroquinone, retinoids, corticosteroids, and kojic acid are clinically proven as exceptionally powerful. However, the adverse effects reported with these small molecules largely impact skin appearance, dermatitis, and exogenous ochronosis. Currently, there is a rising trend towards comfortable, fascinating, and well-endured skin depigmenting agents from natural products that might be utilized by a wide populace. Conclusion: This present study aimed at exploring plant and fruit extracts together with their active ingredients as potential multitargeted anti-hyperpigmentation agents with sunscreen properties, tyrosinase inhibition, and skin whitening effects.

Genetic insights into fiber quality, coat color and adaptation in Changthangi and Muzzafarnagri sheep: A comparative skin transcriptome analysis

Changthangi sheep, which inhabit the high-altitude regions of Ladakh, are known for their fine fiber production and are characterized by grey skin and either black or white coats. In contrast, Muzzafarnagri sheep from the plains of Uttar Pradesh produce coarse wool and have white skin and coats. We conducted comparative global gene expression profiling on four biological replicates of skin from each breed. Notably, our analysis identified 149 up-regulated genes and 2,139 down-regulated genes in Changthangi sheep compared to Muzzafarnagri sheep, with a p-adjusted value (padj) of ≤0.05 and a Log2 fold change of ≥1.5. Gene Ontology analysis of the up-regulated genes revealed an enrichment of terms related to melanin biosynthesis and developmental pigmentation. Additionally, enriched KEGG pathways included tyrosine metabolism and metabolic pathways. Among the melanogenesis-related genes that exhibited higher expression in Changthangi sheep were TYR, TYRP1, DCT, SLC45A2, PMEL, MLANA, and OCA2. These findings confirm melanin's role in both the animals' black coat color and UV protection at high-altitude. Furthermore, we observed more pronounced expression of genes related to fiber quality, namely KRTAP6, KRTAP7, KRTAP13, and KRTAP2, in the fine wool-producing sheep from Ladakh. The results of the RNA sequencing were validated using real-time PCR on 10 genes governing fiber quality and coat color, with ACTB and PPIB serving as reference genes. In conclusion, our comparative skin transcriptome analysis of Changthangi and Muzzafarnagri sheep sheds light on the genetic differences associated with distinct phenotypic traits and environmental adaptability, offering valuable insights into the underlying mechanisms.

자근 추출물의 항산화, 항균 및 미백효과에 관한 연구

To improve the utilization value of Lithospermum Root as a cosmetic material, the study investigated the antioxidant, antibacterial activity, intracellular tyrosinase activity, and melanin biosynthesis inhibitory effects of an Lithospermum Root ethanol extract. As a result, the antioxidant effect showed a 72.5% free radical scavenging at a concentration of 10,000 μg/ml, and the free radical scavenging (FSC)50 value was 4815.90 μg/ml. The antibacterial activity showed an inhibitory effect on all skin flora, S. epidermidis (9.3-14.6 mm), E. coli (10.7-14.6 mm), and P. acnes (9.5-15.2 mm). The viability of B16-F10 cells ranged from 104.9% to 110.1% up to a concentration of 1,000 μg/ml, and a whitening experiment was performed based on this result. At a concentration of 1,000 μg/ml, the intracellular tyrosinase activity inhibition rate was 37.28%, and the melanin synthesis inhibition rate was 30.09%. As a result, it was confirmed that the Lithospermum Root ethanol extract has a significant effect on antioxidant, antibacterial activity, and whitening, and thus has high utilization value as a functional whitening raw material for cosmetics. In the future, analysis of the physiologically active components of the ethanol extract of Lithospermum Root, verification of the efficacy of each component's whitening action, and mechanism studies will be considered necessary.

Development of herbal skin care formulations from the hydro-alcoholic extract of Leucas zeylanica (L.) W.T.Aiton

Introduction: Leucas zeylanica (L.) W.T.Aiton is a plant used in traditional medicine as a remedy against several dermatological conditions. The high UV-filtering potential observed for the aqueousmethanolic extract of this plant suggests its suitability to develop herbal skin care agents. Therefore, this study was undertaken to develop herbal skin care formulations from the aqueous methanolic (hydro-alcoholic) extract of the whole plants of L. zeylanica and evaluate the photoprotective efficacy. Methodology: Three formulations were prepared by incorporating different concentrations (25%, 50%, and 75%) of the extract into an aqueous cream base. Thereafter, the UV filtering potential and sun protection factor (SPF) were determined. Results: The formulation comprised of 75% of the extract displayed the highest UV absorbance as well as the highest SPF value (26.76±3.82). All formulations in general exhibited good photostability profiles. The anti-tyrosinase assay revealed very mild tyrosinase inhibitory potential of the aqueous methanolic extract of L. zeylanica. Therefore our formulations do not interfere with the biosynthesis of melanin, the natural photoprotectant molecule in the skin, unlike most commercial sunscreens. Conclusion: The strong and broad-range UV-filtering potential, high SPF and photostability profiles observed for the sunscreen formulation comprised of 75% of the extract suggest the potential utility of L. zeylanica extract for the development of herbal skin care formulations in a commercial scale.

Albinism in the common shrew Sorex araneus

AbstractAlbinism is a hypopigmentation disorder which occurs as a consequence of mutations in genes involved in melanin biosynthesis. It is recorded in many mammalian species but is generally considered to be rare in natural populations. Here, we describe a fully albino individual of the common shrew Sorex araneus found in south-western Poland. We also present previous findings of albino specimens of this species in Europe. Since the 1960s, there have only been three confirmed records of wholly albino individuals of common shrews in mainland Europe; however, albinism has been recorded more frequently in this species from Britain. In other shrew species, wholly albino individuals are also recorded very rarely.

Rapid, high-titer biosynthesis of melanin using the marine bacterium Vibrio natriegens.

Melanin is one of the most abundant natural biomolecules on Earth. These macromolecular biopolymers display several unique physical and chemical properties and have garnered interest as biomaterials for various commercial and industrial applications. To this end, extensive research has gone into refining methods for the synthesis and extraction of melanin from natural and recombinant sources. In this study, we developed and refined a procedure using a recombinant microbial system for the biosynthesis of melanin using the tyrosinase enzyme Tyr1 and tyrosine as a substrate. Using the emergent microbial chassis organisms Vibrio natriegens, we achieved maximal yields of 7.57g/L, and one of the highest reported volumetric productivities of 473mgL-1 h-1 with 100% conversion rates in an optimized, minimally defined medium. Additionally, we identified and investigated the use of a native copper responsive promoter in V. natriegens for stringent regulation of heterologous protein expression as a cost effective alternative to traditional IPTG-based induction. This research represents a promising advancement towards a green, rapid, and economical alternative for the biomanufacture of melanin.

Penicillium roqueforti Secondary Metabolites: Biosynthetic Pathways, Gene Clusters, and Bioactivities

Penicillium roqueforti is a fungal starter culture used for the production of blue-veined cheeses, such as Roquefort, Gorgonzola, Stilton, Cabrales, and Danablue. During ripening, this species grows in the veins of the cheese, forming the emblematic blue-green color and establishing the characteristic flavor owin to its biochemical activities. P. roqueforti synthesizes a diverse array of secondary metabolites, including the well-known compounds roquefortine C, clavine alkaloids, such as isofumigaclavine A and B, mycophenolic acid, andrastin A, and PR-toxin. This review provides an in-depth exploration of P. roqueforti’s secondary metabolites, focusing on their biosynthetic pathways, the gene clusters responsible for their production, and their bioactivities. The presence of these compounds in blue cheeses is also reviewed. Furthermore, the silent clusters and the potential of P. roqueforti for producing secondary metabolites were discussed. The review highlights recently identified metabolites, including sesterterpenoids; tetrapeptides, D-Phe-L-Val-D-Val-L-Tyr, and D-Phe-L-Val-D-Val-L-Phe; cis-bis(methylthio)silvatin; and the 1,8-dihydroxynaphthalene (DHN)-melanin precursor, scytalone. Additionally, a gene cluster for DHN–melanin biosynthesis is presented. Finally, a revised cluster for roquefortine C biosynthesis comprising three rather than four genes is proposed.

Genome-wide association study (GWAS) analysis of black color trait in the leopard coral grouper (Plectropomus leopardus) using whole genome resequencing

The leopard coral grouper (Plectropomus leopardus) is a coral reef fish species that exhibits rapid and diverse color variation. However, the presence of melanoma and the high proportion of individuals displaying black color in artificial breeding have led to reduced economic and ornamental value. To pinpoint single nucleotide polymorphisms (SNPs) and potential genes linked to the black pigmentation characteristic in this particular species, This study gathered a cohort of 360 specimens from diverse origins and conducted a comprehensive genome-wide association analysis (GWAS) employing whole-genome resequencing. As a result, 57 SNPs related to the black skin trait were identified, and a grand total of 158 genes were annotated within 50 kb of these SNPs. Subsequently, GWAS was applied to three populations (LED, QHH, and QHL), and the corresponding results were compared with the analysis results of the total population. The results of the four GWAS models showed significant enrichment in Rap1 signaling pathway, melanin biosynthesis, metabolic pathways, tyrosine metabolism, cAMP signaling pathway, AMPK signaling pathway, PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, HIF-1 signaling pathway, Ras signaling pathway, MAPK signaling pathway, etc. (p < 0.05), which were mainly associated with eleven genes (POL4, MET, E2F2, COMT, ZBED1, TYRP2, FOXP2, THIKA, LORF2, MYH16 and SOX2). Significant differences (p < 0.05) were observed in the expression of all 11 genes in the dorsal skin tissue, in 10 genes except COMT in the ventral skin tissue, and in all 11 genes in the caudal fin tissue. These findings imply that the control of body color in the P. leopardus is the result of the joint action of multiple genes and signaling pathways. These findings will contribute to a more profound comprehension of the genetic attributes that underlie the development of black skin in the vibrant P. leopardus, thus furnishing a theoretical foundation for genetic enhancement.

Antityrosinase Activity of Phycocyanin and Cream Formulation for Hyperpigmentation

Free radicals are involved in the catalytic reactions of tyrosinase to give dopaquinone in melanin biosynthesis. Screening of molecules with antioxidant activity from natural sources which inhibit tyrosinase has become important for cosmetic and medicinal topical products. Tyrosinase inhibitors are used in treating hyperpigmentation. Synthetic tyrosinase inhibitors possess side effects such as skin irritation, dermatitis, dryness, and inflammatory reaction. The objective of the study is to evaluate the tyrosinase inhibition potential of phycocyanin, which is a pigment extracted from the blue green algae Spirulina platensis and formulating a cream that can be used to treat hyperpigmentation. Phycocyanin possesses anticancer, antioxidant, antiviral and anti-inflammatory activities and exhibits the regulative ability of tyrosinase expression and thereby modulates melanogenesis. The spectral characterization of phycocyanin is carried out using UV-vis spectroscopy, FTIR and HPTLC. Phycocyanin showed tyrosinase inhibition potential with an IC50 of 30.88-39.87 μg/ml in SK-Mel-28 melanoma cells. In melanogenesis pathway, tyrosinase regulates the production of melanin by the skin cells and by incorporating phycocyanin in cream will reduce the melanin production and treat hyperpigmentation.

Computational methods to analyze and predict the binding mode of inhibitors targeting both human and mushroom tyrosinase

Tyrosinase, a copper-containing enzyme critical in melanin biosynthesis, is a key drug target for hyperpigmentation and melanoma in humans. Testing the inhibitory effects of compounds using tyrosinase from Agaricus bisporus (AbTYR) has been a common practice to identify potential therapeutics from synthetic and natural sources. However, structural diversity among human tyrosinase (hTYR) and AbTYR presents a challenge in developing drugs that are therapeutically effective. In this study, we combined retrospective and computational analyses with experimental data to provide insights into the development of new inhibitors targeting both hTYR and AbTYR. We observed contrasting effects of Thiamidol™ and our 4-(4-hydroxyphenyl)piperazin-1-yl-derivative (6) on both enzymes; based on this finding, we aimed to investigate their binding modes in hTYR and AbTYR to identify residues that significantly improve affinity. All the information led to the discovery of compound [4-(4-hydroxyphenyl)piperazin-1-yl](2-methoxyphenyl)methanone (MehT-3, 7), which showed comparable activity on AbTYR (IC50 = 3.52 μM) and hTYR (IC50 = 5.4 μM). Based on these achievements we propose the exploitation of our computational results to provide relevant structural information for the development of newer dual-targeting molecules, which could be preliminarily tested on AbTYR as a rapid and inexpensive screening procedure before being tested on hTYR.

Highly efficient gene knockout system in the maize pathogen Colletotrichum graminicola using Agrobacterium tumefaciens-mediated transformation (ATMT)

Colletotrichum graminicola, a hemibiotrophic pathogenic fungus, is the causal agent of anthracnose of maize, which causes significant yield losses worldwide, especially in warm and humid maize production regions. An efficient targeted genes knockout protocol is crucial to explore molecular mechanisms of fungal virulence to the host. In this study, we established a gene knockout transformation system by employing Agrobacterium tumefaciens-mediated transformation to knockout genes in M 1.001 strain of C. graminicola. The conidia germination status, induction medium type, and ratio of Agrobacterium cell and conidia suspension were optimized for the knockout of CgBRN1(OR352905), a gene relating to the fungal melanin biosynthesis pathway. Additionally, CgPKS18 (OR352906) and CgCDC25 (OR352903) were knocked out to test the applicability of the gene knockout transformation system. In this established system, transformation efficiency was 176 transformants per 1 × 105 conidia and the homologous recombination efficiency was 53.3 to 75%. Furthermore, disease index, lesion number and lesion size caused by the three above-mentioned mutant strains were found to be reduced significantly compared to the wild-type strain, which indicated reduction in fungal virulence due to the lack of those genes.

Deficiency of the melanin biosynthesis genes CfSCD1 impedes appressoria formation and disrupts Colletotrichum fructicola infection on apple

Deficiency of the melanin biosynthesis genes CfSCD1 impedes appressoria formation and disrupts Colletotrichum fructicola infection on apple

Loss of the accessory chromosome converts a pathogenic tree-root fungus into a mutualistic endophyte

Some fungal accessory chromosomes (ACs) may contribute to virulence in plants. However, the mechanisms by which ACs determine specific traits associated with lifestyle transitions along a symbiotic continuum are not clear. Here we delineated the genetic divergence in two sympatric but considerably variable isolates (16B and 16W) of the poplar-associated fungus Stagonosporopsis rhizophilae. We identified a ∼0.6-Mb horizontally acquired AC in 16W that resulted in a mildly parasitic lifestyle in plants. Complete deletion of the AC (Δ16W) significantly altered the fungal phenotype. Specifically, Δ16W was morphologically more similar to 16B, showed enhanced melanization, and established beneficial interactions with poplar plants, thereby acting as a dark septate endophyte. RNA sequencing (RNA-seq) analysis showed that AC loss induced the upregulation of genes related to root colonization and biosynthesis of indole acetic acid and melanin. We observed that the AC maintained a more open status of chromatin across the genome, indicating an impressive remodeling of cis-regulatory elements upon AC loss, which potentially enhanced symbiotic effectiveness. We demonstrated that the symbiotic capacities were non-host-specific through comparable experiments on Triticum– and Arabidopsis–fungus associations. Furthermore, the three isolates generated symbiotic interactions with a nonvascular liverwort. In summary, our study suggests that the AC is a suppressor of symbiosis and provides insights into the underlying mechanisms of mutualism with vascular plants in the absence of traits encoded by the AC. We speculate that AC-situated effectors and other potential secreted molecules may have evolved to specifically target vascular plants and promote mild virulence.

Antioxidant and Tyrosinase Inhibitory Activities of Athamanta sicula L. Aqueous Extract

Introduction: Overexpression of tyrosinase in humans causes an increase in melanin production in the skin, which can result in hyperpigmentation consequences such as freckles, melasma, age spots, and melanoma. Free radicals also play a significant role in the increase of the biosynthesis of melanin. Tyrosinase inhibitors capable of inhibiting the biosynthesis of melanin are currently used in various hyperpigmentation and cosmetic agents to control the formation of freckles. Several synthetic tyrosinase inhibitors have been associated with several serious side effects. Also, synthetic antioxidants have many toxicological side effects, including carcinogenicity. There is an increasing interest in the search for natural tyrosinase inhibitors and antioxidant agents. Aims: The objective of this study is to evaluate total polyphenol and flavonoid contents as well as examine the antioxidative and tyrosinase inhibitory effects of A. sicula L. aqueous extract. Methods: Antioxidant activities were evaluated using superoxide radical scavenging and reducing power methods. Moreover, a tyrosinase inhibitory assay was used to determine anti-hyperpigmentation. Results: The results showed that this extract was rich in total polyphenols (58.01 ± 1.18 micrograms of gallic acid equivalents per milligrams of extract) and flavonoids (17.91 ± 1.81 micrograms quercetin equivalents per milligram of extract). A. sicula L. aqueous extract was capable of scavenging free radicals (IC50 = 11.87 ± 0.13 μg/mL) and acting as a strong reducing agent (A 0.5= 6.37 ± 0.42 μg/mL). A. sicula L. had a potent tyrosinase inhibitory potential (IC50= 12.63 ± 1.15 μg/mL), which was higher compared to kojic acid used as a standard (IC50= 25,23 ± 0,78 μg/mL, p &lt;0.001). Conclusion: These results support that A. sicula L. could be a new source of antioxidant and cosmetic use. Further studies focusing on the isolation and characterization of active principles of antioxidant and tyrosinase inhibitory activities are needed.

Ruta graveolens: Boost Melanogenic Effects and Protection against Oxidative Damage in Melanocytes.

Vitiligo, an acquired depigmentation disorder, is characterized by the loss of functional melanocytes and epidermal melanin. In recent years, research has focused on promoting melanin biosynthesis and protecting melanocytes to reduce stress-related damage for the purpose of applying it to vitiligo treatment. Ruta graveolens L. has been utilized as a medicinal herb in diverse traditional medicine systems to address conditions like vitiligo. In this investigation, we isolated and purified 16 unique alkaloid compounds from the chloroform extracts of R. graveolens, encompassing a new quinoline alkaloid and several recognized compounds. Bioactivity analysis showed that compound 13, an alkaloid derived from R. graveolens, promotes melanin production while protecting PIG3V melanocytes against 4-tert-butylphenol (4-TBP)-induced oxidative damage by downregulating endoplasmic reticulum (ER) stress and pro-inflammatory cytokines through interleukin-6 (IL-6) regulation. Additionally, the compound suppressed the expression of Bip, IRE1, p-IRE1, and XBP-1 proteins, suggesting a potential antioxidant function. These findings suggest that compound 13 isolated from R. graveolens can augment melanogenesis in melanocytes, reduce endoplasmic reticulum (ER) stress, and ameliorate vitiligo exacerbation. The melanogenic activity observed in the chloroform fraction emphasizes R. graveolens's potential as a novel therapeutic target for vitiligo treatment, warranting further exploration in future studies.

Efficient multiple gene knockout in Colletotrichum higginsianum via CRISPR/Cas9 ribonucleoprotein and URA3-based marker recycling.

Colletotrichum higginsianum is a hemibiotrophic pathogen that causes anthracnose disease on crucifer hosts, including Arabidopsis thaliana. Despite the availability of genomic and transcriptomic information and the ability to transform both organisms, identifying C. higginsianum genes involved in virulence has been challenging due to recalcitrance to gene targeting and redundancy of virulence factors. To overcome these obstacles, we developed an efficient method for multiple gene disruption in C. higginsianum by combining CRISPR/Cas9 and a URA3-based marker recycling system. Our method significantly increased the efficiency of gene knockout via homologous recombination by introducing genomic DNA double-strand breaks. We demonstrated the applicability of the URA3-based marker recycling system for multiple gene targeting in the same strain. Using our technology, we successfully targeted two melanin biosynthesis genes, SCD1 and PKS1, which resulted in deficiency in melanization and loss of pathogenicity in the mutants. Our findings demonstrate the effectiveness of our methods in analysing virulence factors in C. higginsianum, thus accelerating research on plant-fungus interactions.

Tyrosinase Inhibitors: A Perspective.

Due to its integral role in the biosynthesis of melanin in all kingdoms of life, tyrosinase has become an extremely important target for inhibition in several sectors of research including agricultural and cosmetic research. Inhibitors of tyrosinase have made it to the market in the cosmetics industry, but their use has been limited due to conflicting efficacy and potential toxicity, which has led to several small molecules being removed from the market. Undaunted, researchers have continued to pursue tyrosinase inhibitors with varying degrees of success. These pursuits have built an impressive and rich library of research. This review is intended to provide a perspective of the past twenty years (2003-2023) of research on tyrosinase inhibitors by highlighting exemplar molecules and developments.

Ebony underpins Batesian mimicry in melanic stoneflies.

The evolution of Batesian mimicry - whereby harmless species avoid predation through their resemblance to harmful species - has long intrigued biologists. In rare cases, Batesian mimicry is linked to intraspecific colour variation, in which only some individuals within a population resemble a noxious 'model'. Here, we assess intraspecific colour variation within a widespread New Zealand stonefly, wherein highly melanized individuals of Zelandoperla closely resemble a chemically defended aposematic stonefly, Austroperla cyrene. We assess convergence in the colour pattern of these two species, compare their relative palatability to predators, and use genome-wide association mapping to assess the genetic basis of this resemblance. Our analysis reveals that melanized Zelandoperla overlap significantly with Austroperla in colour space but are significantly more palatable to predators, implying that they are indeed Batesian mimics. Analysis of 194,773 genome-wide SNPs reveals an outlier locus (ebony) strongly differentiating melanic versus non-melanic Zelandoperla. Genotyping of 338 specimens from a single Zelandoperla population indicates that ebony explains nearly 70% of the observed variance in melanism. As ebony has a well-documented role in insect melanin biosynthesis, our findings indicate this locus has a conserved function across deeply divergent hexapod lineages. Distributional records suggest a link between the occurrence of melanic Zelandoperla and the forested ecosystems where the model Austroperla is abundant, suggesting the potential for adaptive shifts in this system underpinned by environmental change.

Klotho: A new therapeutic target in diabetic retinopathy?

Klotho (Kl) is considered an antiaging gene, mainly for the inhibition of the insulin-like growth factor-1 signaling. Kl exists as full-length transmembrane, which acts as co-receptor for fibroblast growth factor receptor, and in soluble forms (sKl). The sKl may exert pleiotropic effects on organs and tissues by regulating several pathways involved in the pathogenesis of diseases associated with oxidative and inflammatory state. In diabetic Patients, serum levels of Kl are significantly decreased compared to healthy subjects, and are related to duration of diabetes. In diabetic retinopathy (DR), one of the most common microvascular complications of type 2 diabetes, serum Kl levels are negatively correlated with progression of the disease. A lot of evidences showed that Kl regulates several mechanisms involved in maintaining homeostasis and functions of retinal cells, including phagocytosis, calcium signaling, secretion of vascular endothelial growth factor A (VEGF-A), maintenance of redox status, and melanin biosynthesis. Experimental data have been shown that Kl exerts positive effects on several mechanisms involved in onset and progression of DR. In particular, treatment with Kl: (1) Prevents apoptosis induced by oxidative stress in human retinal endothelial cells and in retinal pigment epithelium (RPE) cells; (2) reduces secretion of VEGF-A by RPE cells; and (3) decreases subretinal fibrosis and preserves autophagic activity. Therefore, Kl may become a novel biomarker and a good candidate for the treatment of DR.

Ginsenoside Re inhibits melanogenesis and melanoma growth by downregulating microphthalmia-associated transcription factor

Panax ginseng, also known as Korean ginseng, is a traditional remedy widely used in Asian countries. Its major active compounds are ginsenosides, specifically triterpenoid saponins. Among them, one notable ginsenoside called Re has shown various biological effects, including anti-cancer and anti-inflammatory properties. However, the potential beneficial effects of Re on melanogenesis and skin cancer remain poorly understood. To investigate this, we conducted a comprehensive study using biochemical assays, cell-based models, a zebrafish pigment formation model, and a tumor xenograft model. Our results revealed that Re effectively inhibited melanin biosynthesis in a dose-dependent manner by competitively inhibiting the activity of tyrosinase, an enzyme involved in melanin production. Moreover, Re significantly reduced the mRNA expression levels of microphthalmia-associated transcription factor (MITF), a key regulator of melanin biosynthesis and melanoma growth. Furthermore, Re decreased the protein expression of MITF and its target genes, including tyrosinase, TRP-1, and TRP-2, through a partially ubiquitin-dependent proteasomal degradation mechanism, mediated by the AKT and ERK signaling pathways. These findings indicate that Re exerts its hypopigmentary effects by directly inhibiting tyrosinase activity and suppressing its expression via MITF. Additionally, Re demonstrated inhibitory effects on skin melanoma growth and induced tumor vascular normalization in our in vivo experiments. This study represents the first evidence of Re-mediated inhibition of melanogenesis and skin melanoma, shedding light on the underlying mechanisms. These promising preclinical findings warrant further investigation to determine the suitability of Re as a natural agent for treating hyperpigmentation disorders and skin cancer.