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Melanogenesis is a process to synthesize melanin, which is a primary responsible for the pigmentation of human skin, eye and hair. Although numerous enzymatic catalyzed and chemical reactions are involved in melanogenesis process, the enzymes such as tyrosinase and tyrosinase-related protein-1 (TRP-1) and TRP-2 played a major role in melanin synthesis. Specifically, tyrosinase is a key enzyme, which catalyzes a rate-limiting step of the melanin synthesis, and the downregulation of tyrosinase is the most prominent approach for the development of melanogenesis inhibitors. Therefore, numerous inhibitors that target tyrosinase have been developed in recent years. The review focuses on the recent discovery of tyrosinase inhibitors that are directly involved in the inhibition of tyrosinase catalytic activity and functionality from all sources, including laboratory synthetic methods, natural products, virtual screening and structure-based molecular docking studies.

As a main part of pigmentation disorders, skin depigmentation diseases such as vitiligo and achromic naevus are very common and get more attention now. The pathogenesis of depigmentation includes melanocyte dysfunction and loss, which are possibly caused by heredity, autoimmunity and oxidative stress. Among them, oxidative stress plays a key role; however, few clinical treatments can deal with oxidative stress. As reported, Cistanche deserticola polysaccharide (CDP) is an effective antioxidant; based on that, we evaluated its role in melanocyte and further revealed the mechanisms. In this study, we found that CDP could promote melanogenesis in human epidermal melanocytes (HEMs) and mouse melanoma B16F10 cells, it also induced pigmentation in zebrafish. Furthermore, CDP could activate mitogen‐activated protein kinase (MAPK) signal pathway, then up‐regulated the expression of microphthalmia‐associated transcription factor (MITF) and downstream genes TYR, TRP1, TRP2 and RAB27A. Otherwise, we found that CDP could attenuate H2O2‐induced cytotoxicity and apoptosis in melanocytes. Further evidence revealed that CDP could enhance NRF2/HO‐1 antioxidant pathway and scavenge intracellular ROS. In summary, CDP can promote melanogenesis and prevent melanocytes from oxidative stress injury, suggesting that CDP helps maintain the normal status of melanocytes. Thus, CDP may be a novel drug for the treatment of depigmentation diseases. Cistanche deserticola polysaccharide (CDP) promotes melanogenesis in human epidermal melanocytes via activating mitogen‐activated protein kinase (MAPK) signal pathway, then up‐regulates the expression of MITF, TYR, TRP1, TRP2, and RAB27A. Otherwise, CDP can attenuate H2O2‐induced oxidative stress in melanocytes via enhancing NRF2/HO‐1 antioxidant pathway and scavenge intracellular ROS.

Acne vulgaris is a common inflammatory disease. Among patients with darker skin phototypes (Fitzpatrick III–VI), the inflammatory processes of acne stimulate excess melanogenesis and abnormal melanin deposition, leading to pigmentary sequelae known as post-inflammatory hyperpigmentation and post-inflammatory erythema in all skin tones, although post-inflammatory hyperpigmentation is more common in darker skin and post-inflammatory erythema in lighter skin. These pigmentary alterations can be long lasting and are often more distressing to patients than the active acne lesions. This article discusses what is known about acne-related pigmentation, much of which is extrapolated from general study of nonspecific pigment deposition. Because dyspigmentation poses both a significant clinical concern to patients and a therapeutic challenge to clinicians, we formed a working group consisting of pigmentary experts with the aim of increasing awareness and education of acne-related pigmentary sequelae.

The excessive synthesis of melanin leads to skin hyperpigmentation. While tyrosinase activity inhibition has demonstrated efficacy in ameliorating hyperpigmentation, its effectiveness remains limited, and tyrosinase inhibitors may induce irritant contact dermatitis. Therefore, there is an imperative need to develop safer and more potent anti-pigmentation agents. Melanin transfer inhibition represents a novel therapeutic strategy for treating hyperpigmentation. This review systematically elucidates the complete process of melanin transfer and its underlying mechanisms. Furthermore, it provides a comprehensive analysis of natural products and small molecule compounds with melanin transfer-inhibiting capabilities, potential compounds that may exhibit anti-pigmentation effects, as well as the binding modes and structure-activity relationships (SARs) of representative compounds. The presented evidence is crucial for identifying and developing novel, highly effective anti-pigmentation medications.

Coreopsis tinctoria Nutt. is an important medicinal plant in traditional Uyghur medicine. The skin-lightening potential of the flower has been recognized recently; however, the active compounds responsible for that are not clear. In this work, tyrosinase, a target protein for regulating melanin synthesis, was immobilized on the Whatman paper for the first time to screen skin-lightening compounds present in the flower. Quercetagetin-7-O-glucoside (1), marein (2), and okanin (3) were found to be the enzyme inhibitors. The IC50 values of quercetagetin-7-O-glucoside (1) and okanin (3) were 79.06 ± 1.08 μM and 30.25 ± 1.11 μM, respectively, which is smaller than 100.21 ± 0.11 μM of the positive control kojic acid. Enzyme kinetic analysis and molecular docking were carried out to investigate their inhibition mechanism. Although marein (2) showed a weak inhibition effect in vitro, it inhibited the intracellular tyrosinase activity and diminished melanin production in melanoma B16 cells as did the other two inhibitors. The paper-based ligand fishing method developed in this work makes it effective to quickly screen tyrosinase inhibitors from natural products. This is the first report on the tyrosinase inhibitory effect of those three compounds, showing the promising potential of Coreopsis tinctoria for the development of herbal skin-lightening products.

Inspired by the potent tyrosinase inhibitory activity of phenolic compounds with a 2-phenylbenzo[d]thiazole scaffold, we explored phenolic compounds 1–15 with 2-phenylbenzo[d]oxazole, which is isosterically related to 2-phenylbenzo[d]thiazole, as novel tyrosinase inhibitors. Among these, compounds 3, 8, and 13, featuring a resorcinol structure, exhibited significantly stronger mushroom tyrosinase inhibition than kojic acid, with compound 3 showing a nanomolar IC50 value of 0.51 μM. These results suggest that resorcinol plays an important role in tyrosinase inhibition. Kinetic studies using Lineweaver–Burk plots demonstrated the inhibition mechanisms of compounds 3, 8, and 13, while docking simulation results indicated that the resorcinol structure contributed to tyrosinase binding through hydrophobic and hydrogen bonding interactions. Additionally, these compounds effectively inhibited tyrosinase activity and melanin production in B16F10 cells and inhibited B16F10 tyrosinase activity in situ in a concentration-dependent manner. As these compounds showed no cytotoxicity to epidermal cells, melanocytes, or keratinocytes, they are appropriate for skin applications. Compounds 8 and 13 demonstrated substantially higher depigmentation effects on zebrafish larvae than kojic acid, even at 800- and 400-times lower concentrations than kojic acid, respectively. These findings suggest that 2-phenylbenzo[d]oxazole is a promising candidate for tyrosinase inhibition.

Melanogenesis, the key biological process underlying skin hyperpigmentation, is tightly regulated by complex molecular signaling pathways. Consequently, targeting molecular regulators of this pathway is a crucial strategy for developing effective skin-whitening agents. Cannabinol (CBN), a minor cannabinoid, has been largely unexplored owing to its role in modulating skin pigmentation. This study aimed to elucidate the molecular mechanisms of CBN’s depigmenting effects using an α-MSH-induced B16F10 melanoma cell model. High-purity CBN was obtained via conversion of cannabidiol (CBD) and confirmed by HPLC. CBN significantly inhibited melanin synthesis and tyrosinase activity in a concentration-dependent manner, without any cytotoxicity. Furthermore, we investigated CBN’s impact on the melanogenesis signaling cascade. Our analysis revealed that CBN significantly downregulated the mRNA and protein levels of key melanogenic master regulators, including MITF, TYR, TYRP1, and TYRP2. Importantly, we also observed that CBN treatment selectively suppressed the protein phosphorylation of upstream signaling molecules such as p38 and JNK MAP kinases and NF-κB, while ERK phosphorylation remained unaffected. This finding indicates that its mechanism of action involves the selective modulation of pro-melanogenic signaling components. Collectively, these findings demonstrate that CBN effectively modulates the melanogenesis signaling pathway by targeting both upstream kinases and downstream melanogenic genes. These findings suggest that CBN holds great promise as a bioactive agent for skin-whitening applications and warrants further research to confirm its clinical efficacy and safety.

Based on the fact that substances with a β-phenyl-α,β-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs 1–8 were prepared as potential tyrosinase inhibitors. Four analogs (1–3 and 5) inhibited mushroom tyrosinase strongly. Especially, analog 3 showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs 1 and 3 competitively inhibited tyrosinase, whereas analogs 2 and 5 inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs 2 and 5 could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs 1, 3, and 5 effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs 1, 3, and 5 inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs 2 and 3 exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders.

Tyrosinase, a copper-containing glycoprotein, is the rate-limiting enzyme critical for melanin biosynthesis in specialized organelles termed melanosomes that are produced only by melanocytic cells. Inhibitors of tyrosinase activity have long been sought as therapeutic means to treat cutaneous hyperpigmentary disorders. Multiple potential approaches exist that could control pigmentation via the regulation of tyrosinase activity, for example: the transcription of its messenger RNA, its maturation via glycosylation, its trafficking to melanosomes, as well as modulation of its catalytic activity and/or stability. However, relatively little attention has been paid to regulating pigmentation via the stability of tyrosinase, which depends on its processing and maturation in the endoplasmic reticulum and Golgi, its delivery to melanosomes and its degradation via the ubiquitin-proteasome pathway and/or the endosomal/lysosomal system. Recently, it has been shown that carbohydrate modification, molecular chaperone engagement, and ubiquitylation all play pivotal roles in regulating the degradation/stability of tyrosinase. While such processes affect virtually all proteins, such effects on tyrosinase have immediate and dramatic consequences on pigmentation. In this review, we classify melanogenic inhibitory factors in terms of their modulation of tyrosinase function and we summarize current understanding of how the quality control of tyrosinase processing impacts its stability and melanogenic activity.

2,5-dihydroxyacetophenone, a natural product from the fruiting bodies of , can effectively and safely inhibit the production of melanin in zebrafish model. To achieve analogues with more significant inhibition, 9 analogs were synthesised and 13 analogues were purchased commercially. Among them, 14 compounds can inhibit melanin production, of which 5 compounds displayed the most significant inhibitory effects, with inhibitory rates of more than 80%, compared to positive control SymWhite 377 (phenylethyl resorcinol). This study elucidated the melanin-inhibitory effects of 2,5-dihydroxyacetophenone and its analogs, providing a theoretical foundation for their potential applications in anti-melanogenic reagents.