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Melanin Pigmentation: Physiology and Pathology

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 March 2026 | Viewed by 4060

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Special Issue Editors

Prof. Dr. Shosuke Ito

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Guest Editor

Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi, Japan
Interests: structure and properties of melanins; chemistry of melanogenesis; chemical analysis of melanins; effects of ultraviolet radiation and visible light on melanins; effects of heat on melanins; chemistry of tyrosinase-catalyzed oxidation of phenols
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Prof. Dr. Manickam Sugumaran

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Guest Editor

Department of Biology, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, USA
Interests: enzymology; post translational modifications; aromatic metabolism; phenolic biochemistry; reactions of quinonoid compounds; invertebrate immunity; insect cuticular sclerotization; phenoloxidase; quinone isomerases; oxidative browning; melanin biosynthesis; catecholic antibiotics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Melanins are a group of biopolymeric phenolic pigments ubiquitously present in most organisms. In mammals and birds, two types of melanin are found, the brown-to-black insoluble eumelanin and the reddish-brown, sulfur-containing pheomelanin. They are produced within melanocytes through the tyrosinase-catalyzed oxidation of tyrosine. In addition, we are aware of extracutaneous melanins, such as substantia nigra neuromelanin. Studies have disclosed a variety of physiological roles for eumelanin, such as photoprotection, antioxidant defense, and drug/metal binding. On the contrary, pheomelanin is believed to be pro-oxidant and phototoxic, leading to melanoma development. Many factors are involved in the melanogenic pathway, and the dysregulation of these control mechanisms results in pigmentary disorders, from melasma to vitiligo.

Contributions to this Special Issue may cover any aspect of the chemistry of natural and synthetic melanins with potential practical applications; melanogenesis inhibition through the definition of its mechanism of action; approaches to the amelioration or control of any type of melanin-based pigmentary disorder, as well as photoprotection strategies; innovative methodologies for the analysis of pigmented tissues and for diagnostic purposes; molecular engineering methodologies for melanin production in microorganisms; and novel functions of melanins that are of potential interest for applications, drug targeting, and exploiting the specific affinities of melanins.

Experimental papers and up-to-date review articles are welcome.

Prof. Dr. Shosuke Ito
Prof. Dr. Manickam Sugumaran
Guest Editors

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Keywords

eumelanin
pheomelanin
melanogenesis
photoprotection
pigmentary disorders
depigmenting agents
extracutaneous melanins

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Published Papers (6 papers)

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18 pages, 1030 KB

Open AccessArticle

Targeting Melanin Production: The Safety of Tyrosinase Inhibition

by Steffen Erler, Ludger Kolbe, Abdulkarim Najjar, Andreas Schepky, Ahmed Kamal, Daniela Lange and Tamara Rogers

Int. J. Mol. Sci. 2026, 27(1), 97; https://doi.org/10.3390/ijms27010097 (registering DOI) - 22 Dec 2025

Abstract

Hyperpigmentation remains a persistent dermatological challenge with limited treatment options. Among available strategies, tyrosinase inhibition stands out as the current most effective and safest approach for suppressing melanin synthesis. Thiamidol exemplifies a targeted tyrosinase inhibitor developed over a decade of research, guided by rigorous toxicological evaluation. Although it contains a resorcinol moiety, Thiamidol is not a resorcinol derivative and acts through a distinct thiazole 2-amino moiety. In addition to its targeted mode of action of tyrosinase inhibition rather than inactivation, assessments of cytotoxicity and genotoxicity distinguish it from cosmetic and pharmaceutical active ingredients that form highly reactive ortho- or para-quinones. With further exclusion for off-target effects based on pharma profiling and exposure modeling, Thiamidol’s rapid metabolism and absence of bioaccumulation support its safety profile. While an inhibitory mechanism requires repeated application, this characteristic enhances the safety profile and establishes Thiamidol as a cosmetic ingredient rather than a pharmaceutical. In additional to confirmatory clinical studies for efficacy and skin compatibility, a study shows that the use of Thiamidol-containing products does not negatively impact the dermatological diagnostic accessibility of naevi, which is important for skin health monitoring. Full article

(This article belongs to the Special Issue Melanin Pigmentation: Physiology and Pathology)

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24 pages, 16860 KB

Open AccessArticle

Mechanistic Insights into Anti-Melanogenic Effects of Fisetin: PKCα-Induced β-Catenin Degradation, ERK/MITF Inhibition, and Direct Tyrosinase Suppression

by Zin Zin Ei, Satapat Racha, Hongbin Zou and Pithi Chanvorachote

Int. J. Mol. Sci. 2025, 26(23), 11739; https://doi.org/10.3390/ijms262311739 - 4 Dec 2025

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Abstract

Excessive melanin production causes hyperpigmentation disorders such as freckles, melasma, and age spots, affecting appearance and quality of life. Tyrosinase is the key enzyme controlling melanin synthesis, and natural compounds are being explored as effective tyrosinase inhibitors. Fisetin, a dietary flavonoid found in fruits and vegetables like grapes and onions, is known for its anti-inflammatory and anticancer properties, but its anti-melanogenic activity remains unclear. This study demonstrated that fisetin, up to 60 μM, is non-toxic and significantly decreases tyrosinase activity and melanin content in human melanoma cells. Mechanistically, fisetin activates PKCα, leading to phosphorylation and degradation of β-catenin, thereby downregulating MITF expression. Additionally, it activates ERK and AKT/GSK3β pathways, promoting ubiquitination and proteasomal degradation of MITF, resulting in reduced levels of tyrosinase, TRP-1, and TRP-2. The proteasome inhibitor MG132 confirmed that fisetin accelerates β-catenin and MITF degradation. Additionally, inhibition of the PI3K/AKT pathway by LY294002 or the ERK pathway by PD98059 reversed fisetin’s reduction of tyrosinase activity and melanin synthesis, further verifying the participation of these pathways. Computational docking integrated with deep learning-based CNN scoring revealed that fisetin interacts with PKCα, β-catenin, tyrosinase, and TYRP1. Collectively, these findings suggest that fisetin exerts multi-targeted inhibitory effects on melanogenesis, highlighting its potential as a therapeutic and cosmetic agent for hyperpigmentation. Full article

(This article belongs to the Special Issue Melanin Pigmentation: Physiology and Pathology)

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14 pages, 2497 KB

Open AccessArticle

A Non-Invasive Approach to Intracellular Measurement in Solar Lentigo: Investigating Mitochondrial Dysfunction and Senescence Mechanisms Associated with Excessive Melanin Deposition

by Alif Meem Nurani, Takako Shibata and Daigo Inoue

Int. J. Mol. Sci. 2025, 26(22), 10918; https://doi.org/10.3390/ijms262210918 - 11 Nov 2025

Viewed by 845

Abstract

Solar lentigo is a significant dermatological concern affecting individuals of different genders and ethnicities. Its pathogenesis is primarily attributed to chronic ultraviolet (UV) exposure, increased melanogenesis, and disrupted epidermal turnover, leading to the development of hyperpigmented lesions. A major challenge in solar lentigo research is acquiring viable skin tissue, which is crucial for understanding the dynamics of the cellular microenvironment. In the present study, we sought to establish a non-invasive in vivo measurement technique to visualize cellular dynamics associated with solar lentigo. Utilizing fluorescence lifetime imaging microscopy (FLIM), we quantified the decay of NAD(P)H fluorescence lifetime and observed a reduction in oxidative phosphorylation (OXPHOS) activity in solar lentigo lesions compared to adjacent non-lesional skin. To determine whether the observed reduction in OXPHOS activity was due to excessive melanin accumulation in keratinocytes, we developed a melanin deposition model and examined the pleiotropic alterations occurring in keratinocytes following the phagocytosis of excessive melanin. Our findings indicate that excessive melanin deposition downregulates OXPHOS in differentiating keratinocytes and induces senescence-associated phenotypes characterized by perturbed cell cycle progression, increased cell size and aneuploidy, and the secretion of inflammatory mediators in proliferating keratinocytes. Collectively, our results implicate a solar lentigo-specific senescence mechanism driven by excessive melanin accumulation in keratinocytes, providing new insights about the intrinsic modulators of the pathological condition. Full article

(This article belongs to the Special Issue Melanin Pigmentation: Physiology and Pathology)

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13 pages, 4972 KB

Open AccessArticle

Mechanistic Insights into Tyrosinase-Catalyzed Metabolism of Hydroquinone: Implications for the Etiology of Exogenous Ochronosis and Cytotoxicity to Melanocytes

by Shosuke Ito, Ludger Kolbe, Tamara Rogers, Tobias Mann, Gudrun Weets, Hitomi Tanaka, Tomoko Nishimaki-Mogami, Thierry Passeron, Makoto Ojika and Kazumasa Wakamatsu

Int. J. Mol. Sci. 2025, 26(21), 10734; https://doi.org/10.3390/ijms262110734 - 4 Nov 2025

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Abstract

The metabolism of hydroquinone (HQ) by tyrosinase presents significant biochemical and dermatological challenges, particularly due to its association with adverse effects such as exogenous ochronosis (EO). Despite its widespread use in skin-lightening products, the detailed mechanistic pathways of HQ metabolism by tyrosinase remain inadequately understood. This study aims to elucidate the mechanistic insights into the tyrosinase-catalyzed metabolism of HQ, leading to the production of HQ-eumelanin (HQ-EM) and HQ-pheomelanin (HQ-PM). We employed HPLC analysis to detect key intermediates and final metabolites. Results show that mushroom tyrosinase catalyzes the hydroxylation of HQ to 2-hydroxyhydroquinone (HHQ) via the 2-hydroxybenzoquinone (HBQ) pathway, giving rise to HQ-EM. However, in the presence of cysteine, a shift from HBQ to the benzoquinone (BQ) pathway occurs, giving rise to HQ-PM. Hydroiodic acid hydrolysis of HQ-PM and subsequent HPLC-electrochemical analysis identified 4-aminophenol (AP) as degradation product, thereby serving as a novel marker to monitor HQ oxidation in vitro. These results indicate that HQ functions both as a “pseudo” substrate for tyrosinase—undergoing redox exchange with dopaquinone to form BQ—and as a true substrate, yielding HBQ. This dual role contributes to the formation of HQ-EM and HQ-PM. It would be possible that EO is caused by a continuous oxidation of HQ mediated by tyrosinase activity in the skin. Full article

(This article belongs to the Special Issue Melanin Pigmentation: Physiology and Pathology)

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15 pages, 2409 KB

Open AccessArticle

Over-Represented Senescent Keratinocytes in Hyperpigmented Spots Promote Melanocyte Activation via IGFBP3 and NGF

by Tomohiro Hakozaki, Holly Rovito, Bradley B. Jarrold, John Snowball, Jiazhen Wang, Wenzhu Zhao and Timothy Laughlin

Int. J. Mol. Sci. 2025, 26(21), 10724; https://doi.org/10.3390/ijms262110724 - 4 Nov 2025

Viewed by 970

Abstract

The occurrence and impact of cellular senescence on skin aging and hyperpigmentation is an ongoing area of exploration, encompassing both intrinsic and extrinsic stressors. Traditionally, research has focused on melanocyte and fibroblast senescence due to their slower turnover compared to keratinocytes. In this study, we identified the accumulation of p16, a senescence marker, in keratinocytes from biopsies of multiple spot types. We explored their impact using doxorubicin-induced senescent keratinocytes in vitro. Conditioned media from these senescent keratinocytes stimulated melanocyte dendricity, a hallmark of hyperpigmented spots. Transcriptomic analysis of senescent keratinocytes identified two key senescence-induced factors: Insulin-like Growth Factor-Binding Protein 3 (IGFBP3) and Nerve Growth Factor (NGF). IGFBP3 and NGF ligand treatment enhanced melanin synthesis by 33% and 17%, and dendricity by 23% and 14%, respectively, in human melanocyte cultures. These findings suggest that keratinocyte senescence contributes to spot formation by mediating melanocyte activation through IGFBP3 and NGF. Furthermore, we evaluated skincare ingredients such as sucrose dilaurate, glabridin, and niacinamide in neutral and low pH solutions, demonstrating their efficacy in reducing the secretion of these ligands, thereby offering potential cosmetic benefits. This study provides insights into the mechanisms of spot formation and highlights promising strategies for managing pigmentation disorders. Full article

(This article belongs to the Special Issue Melanin Pigmentation: Physiology and Pathology)

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8 pages, 758 KB

Open AccessBrief Report

UVB-/Age-Dependent Upregulation of Inflammatory Factor Interleukin-6 Receptor (IL-6R) in Keratinocytes Stimulates Melanocyte Dendricity

by Daigo Inoue, Koji Ohba and Takako Shibata

Int. J. Mol. Sci. 2025, 26(22), 10971; https://doi.org/10.3390/ijms262210971 - 12 Nov 2025

Viewed by 423

Abstract

Ultraviolet (UV) irradiation stimulates melanogenesis in melanocytes and melanin transfer to keratinocytes, where the former is mediated by pleiotropic factors such as SCF, α-MSH, and endothelin-1 (ET-1) secreted by keratinocytes. Therefore, the interaction between melanocytes and keratinocytes after UVB exposure appears to be critical to stimulating melanogenesis. The factors that are responsible for inflammation, one of the key biological processes, are crucial to forming the chronic inflammatory microenvironment in solar lentigines (hereafter called age spots). While chronic inflammation is thought to be involved in hyperpigmentation, the molecular mechanisms through which microinflammation affects melanocyte activation in age spots have not been elucidated. In our study, immunohistochemical analysis showed that the expression of the inflammatory factor IL-6R is enhanced in age spots. Specifically, in cultured keratinocytes irradiated with 10 mJ/cm² UVB, the expression of IL-6R was upregulated in UVB exposure- and age-dependent manners, and the co-culture of melanocytes with UVB-irradiated keratinocytes further demonstrated that melanocyte dendrites increased in length and number in a keratinocyte-age-dependent manner. Moreover, the suppression of IL-6R function in keratinocytes by an IL-6R-specific neutralizing antibody, Tocilizumab, inhibited melanocyte dendricity. These results indicate that the age- and UVB-dependent upregulation of IL-6R in keratinocytes stimulates melanocyte dendricity, which may also contribute to excessive melanin deposition in age spots. Full article

(This article belongs to the Special Issue Melanin Pigmentation: Physiology and Pathology)

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