Pathogenesis of Melasma Explained

ABSTRACT

This review provides an in‐depth analysis of the pathophysiology of melasma and highlights recent studies that elucidate its underlying mechanisms. Given the prevalence of melasma, a thorough understanding of its pathogenesis is critical for the development of effective treatment strategies. We analyzed the current literature to identify findings related to epidermal changes, basement membrane (BM) alterations, and various dermal modifications, including solar elastosis, mast cell activity, and vascular changes. We also examined the influence of visible light (VL) and hormonal fluctuations on melasma. This review intertwines these insights with an overview of contemporary treatment approaches. Our findings indicate advancements in understanding melasma's pathophysiology, highlighting significant changes in the epidermis and BM, along with dermal factors, such as vascular alterations, mast cell involvement, and senescent fibroblasts. We review the established mechanisms in the pathogenesis of melasma while incorporating recent scientific updates. Additionally, a survey of the available treatments targeting these novel mechanisms revealed promising therapeutic modalities currently under investigation. In conclusion, understanding the latest pathophysiological insights is crucial for enhancing clinician awareness and patient reassurance, as well as improving therapeutic strategies. Nevertheless, ongoing research remains essential to elucidate the complexities of melasma further and optimize clinical outcomes.

Pathophysiology of melasma.

1. Introduction

Melasma is a common condition whose pathophysiology and management remain challenging. Understanding melasma's skin landscape and pathogenesis is crucial for navigating current and future therapeutic strategies. Melasma is defined as hypermelanosis of the skin that results in brown‐gray symmetrical patches on the face. Extrafacial melasma occurs but is less common. The average age of onset ranges between 20 and 40 years, with a female‐to‐male prevalence ratio ranging between 4:1 and 39:1 [1].

Melanin, a complex polymer derived from the amino acid tyrosine, is responsible for the pigmentation of the skin, hair, and eyes in mammals [2]. Through melanogenesis, melanin is produced by melanocytes, which are highly differentiated cells in the epidermis and hair follicles, and are packaged and stored in melanosomes [3, 4]. Melanocytes transfer melanin pigments to surrounding keratinocytes in the skin, resulting in its pigmented tone [5].

Multiple intracellular signaling pathways and external stimuli regulate melanogenesis. Various intracellular signaling pathways activate the microphthalmia‐associated transcription factor (MITF) pathway, a crucial melanogenesis regulator. Key intracellular signaling pathways that contribute to MITF activation include cyclic adenosine monophosphate (cAMP)/protein kinase A(PKA), stem cell factor (SCF)/c‐kit, phosphatidylinositol‐3 kinase(PI3K)/protein kinase B (Akt) pathway, nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), and Wnt/β‐catenin [6, 7]. Wnt induces the proliferation of melanocyte stem cells and is associated with increased expression of Wnt signaling‐related genes in patients with melasma [7]. Activation of Wnt receptor complexes leads to the accumulation of β‐catenin [6], which upregulates MITF expression, stimulating melanogenesis [6]. Similarly, SCF binds to receptor tyrosine kinase “c‐kit” which activates the MITF transcription factor, contributing to melanocyte pigmentation and melanogenesis. Genes targeted by the activated MITF further regulate these melanocyte pigmentation processes [8].

The role of MITF in melanin synthesis is highlighted by the effects of various intracellular pathways on its expression. MITF also plays a significant role in the pathogenesis of melasma, since multiple pathways and regulatory substances can upregulate or downregulate melanogenesis. These pathways are interconnected and influenced by external stimuli, including ultraviolet (UV) radiation, hormones, and cytokines.

While ongoing studies continue to explore the underlying pathways, the pathogenesis of melasma involves changes in the epidermis, basement membrane (BM), and dermal layer and includes vascular alterations, solar elastosis, mast cell variations, the presence of senescent fibroblasts in addition to visible light (VL) exposure, and hormonal influences.

2. Epidermal Changes

Historically, melasma was classified according to Wood's lamp examination into dermal, epidermal, and mixed types. While the diagnosis is primarily made clinically, additional tools such as dermoscopy and confocal microscopy are used to aid in the diagnostic process. Furthermore, studies have demonstrated that melasma is often present in the epidermis with a degree of dermal involvement [9]. Increased melanin production in the epidermal layer occurs upon UV exposure [10]. UV radiation upregulates melanocortin 1 receptor (MC1‐R), the melanocyte‐stimulating hormone (MSH) binding site. MC1‐R upregulation enhances its binding capacity to MSH, leading to increased melanin production [10]. Additionally, UV exposure in the epidermal layer cleaves proopiomelanocortin (POMC) into alpha‐melanocyte‐stimulating hormone (alpha‐MSH) and adrenocorticotropic hormone (ACTH) [11] that activate MC1‐R, resulting in phosphorylation of cAMP response element‐binding protein (CREB), which acts as a transcription factor for MITF [10].

UV‐induced melanogenesis involves the tumor suppressor protein p53 [9]. Ultraviolet B (UVB) damage activates p53, which promotes cutaneous pigmentation by activating POMC transcription in the skin, thereby functioning as a transcriptional regulator of the POMC/MSH pathway [12]. Additionally, p53 independently upregulates the transcription of hepatocyte nuclear factor 1‐alpha (TNF‐1 alpha) [6], which induces tyrosinase expression to increase melanin production (Figure 1) [6].

FIGURE 1.

Pathways triggering epidermal changes in melasma pathogenesis: the role of p53 as a transcriptional regulator, activation of pathways post‐UV exposure, subsequent MITF transcription to induce melanin synthesis, and the VL pathways involved in melanogenesis through interactions with photoreceptor Opsin‐3 and disruptions of the circadian rhythm.

MITF regulates the expression of melanogenic enzymes, including tyrosinase and tyrosinase‐related proteins 1 and 2 (TYRP1 and TYRP2) [13]. Tyrosinase is the rate‐limiting enzyme in the melanin synthesis pathway that catalyzes the conversion of dihydroxyphenylalanine (DOPA) [14]. There is a correlation between tyrosinase activity and melanin content in melasma‐affected skin (Figure 1) [13].

Key changes in melanocytes within the epidermal layer of skin with lesional melasma have been observed. Melanocyte activity in patients with melasma differs from that in unaffected skin [15], including having larger melanocytes and more melanosomes. Additionally, biopsied samples not only stain more intensely but also show prominent dendrites when compared to perilesional skin, using a variety of staining techniques [15].

A histochemical study of Korean women with melasma revealed a significant increase in melanin content and melanocyte density in the epidermis compared to perilesional skin [14]. Similarly, another study observed increased melanin deposition in both epidermal and dermal layers, along with larger melanocytes, prominent dendrites, and intensely stained cells [16, 17].

Topical skin‐lightening agents are used to treat hyperpigmentation and excess melanin production in melasma. Hydroquinone (HQ) is a skin‐lightening hydroxyphenolic compound derived from benzene that inhibits tyrosinase and disrupts the conversion of DOPA to melanin [18]. Additionally, HQ affects DNA and RNA synthesis, alters melanosome formation, and induces necrosis of melanocytes. A study comparing 4% HQ to 5% cysteamine over 60–120 days found a mean reduction in the Melasma Area and Severity Index (MASI) score of 24% and 41% at 60 days and 38% and 53% at 120 days for cysteamine and HQ, respectively [19]. Furthermore, HQ can be combined with 0.05% retinoic acid (RA) and corticosteroids, such as 0.01% fluocinolone acetonide or 0.1% dexamethasone (triple combination therapy) [20]. L‐cysteamine exerts its antioxidant and depigmentation properties through the inhibition of tyrosinase and peroxidase and plays a role in the treatment of melasma [19].

Azelaic acid, which is a nonphenolic topical skin‐lightening agent, exhibits anti‐inflammatory properties and downregulates tyrosinase activity while inhibiting reactive oxygen species (ROS) in melanogenesis [21]. The effectiveness of 4% HQ and 20% azelaic acid over 2 months is comparable. However, larger studies are needed to ascertain the true efficacy of azelaic acid in melasma [21].

Niacinamide is a topical skin‐lightening agent with anti‐inflammatory properties and reduces melanosome transfer [22]. A study that compared the effects of niacinamide with 4% HQ showed that 55% of patients had good‐to‐excellent improvement in lesions, while 44% experienced similar results with niacinamide [22].

Thiamidol (isobutylamidothiazolyl resorcinol) is a potent tyrosinase inhibitor that may be used for UV‐induced hyperpigmentation [23]. A randomized controlled trial (RCT) comparing 0.2% Thiamidol with 4% HQ for facial melasma revealed a mean reduction in the modified MASI score of 43% for Thiamidol compared to 33% for HQ [24].

Combination therapy with picosecond lasers has gained traction for its ability to deliver photoacoustic injury with a low photothermal effect while inducing melanin fragmentation [25]. The 1064 nm picosecond laser, combined with topical treatments, significantly lowers MASI scores compared to other laser modalities [26]. Similarly, combining the 755 nm picosecond laser with tranexamic acid (TXA) results in a notable reduction in lesion hyperpigmentation (p < 0.05) [26].

2.1. Epidermal Changes: Pendulous Melanocytes

Pendulous melanocytes refer to melanocytes that extend into the dermal layer. Their distinctive appearance is related to melanocyte hyperactivity in the epidermis and sustained damage to the BM. These melanocytes protrude or “droop” into the dermal layer due to disruptions in the BM caused by matrix metalloproteinases (MMPs) and reduced cadherin expression. Chronic UV exposure leads to overexpression of MMP, breaking down collagen types IV and V in the BM [27], and cadherin, which is vital for the adhesion of keratinocytes to melanocytes [28]. These changes facilitate melanocyte migration into deeper layers, contributing to persistent hyperpigmentation.

A study that evaluated melanocyte hyperactivity and pendulous melanocytes found intensely stained cells with prominent dendrites, indicating hyperactivity. Additionally, 24% of patients had pendulous melanocytes using in vivo RCM [29]. The clinical significance of pendulous melanocytes remains unclear, but they appear to be associated with epidermal melanocyte hyperactivity observed in hyperpigmentation disorders, including simple lentigo and café au lait spots [30].

2.2. Epidermal Changes: Oxidative Stress

Oxidative status contributes to epidermal changes in melasma. Oxidative stress (OS) results from multiple epidermal damage pathways. Hazardous reactive oxygen species (ROS) are byproducts of repetitive exposure to different oxidants [31]. Physiologically, antioxidant‐protective pathways counteract and neutralize ROS. However, these pathways become overwhelmed and saturated with high levels of ROS, resulting in OS followed by tissue damage [32]. OS occurs in patients with inflammation and cancer or secondary to excessive UV radiation and is involved in cutaneous disorders, including psoriasis and skin cancer [33].

Lipid and protein peroxidation produce oxidants. The lipid peroxidation pathway arises from OS, leading to tissue impairment and malondialdehyde (MDA) production, an indicator of tissue injury mediated by free oxygen radicals [34]. MDA‐level measurements have been found to be elevated in patients with melasma compared to those with healthy skin [35].

The protein peroxidation pathway results from the interaction between ROS and proteins, causing oxidative damage to amino acids and leading to the production of protein carbonyl [36, 37].

The skin has enzymatic and nonenzymatic antioxidant protective pathways. Superoxide dismutase (SOD) is a key enzyme in these pathways [32, 38]. SOD converts highly reactive superoxide anions into hydrogen peroxide (H₂O₂), which is generated by coupling with Complexes I and III of the electron transport chain that produce ROS [32].

H₂O₂ is more stable than superoxide anions and can easily diffuse across membranes. Normally, catalase and glutathione peroxidase detoxify H₂O₂ to H₂O and O₂, but this may be disrupted in response to UV‐mediated changes in melanogenesis. Ultraviolet‐A (UVA) induced melanogenesis downregulates catalase activity and reduces glutathione levels [35, 36]. The overproduction of H₂O₂ and nitric oxide (NO) is correlated with UVA‐mediated melanogenesis and OS [35].

NO is a biological signaling mediator and immune modulator synthesized by three isoforms of nitric oxide synthase (NOS): endothelial NOS (eNOS), neuronal NOS, and inducible NOS (iNOS). iNOS is involved in various inflammatory disorders, including melasma, and its activation in basal keratinocytes is associated with melanogenesis [39].

UVB stimulates the PI3K/Akt pathway and NF‐κB, subsequently inducing iNOS expression in keratinocytes and increasing NO production, which acts as a paracrine mediator of melanogenesis by activating tyrosinase [39, 40].

Nonenzymatic antioxidant pathways in the skin involve ascorbic acid (vitamin C), alpha‐tocopherol (vitamin E), and selenium. Vitamin C plays a role in the protective pathways of the skin, has antimelanogenic effects [41], and neutralizes OS through electron transfer and donation while replenishing vitamin E [42].

Vitamin E helps maintain the skin collagen network and protects cell membranes from oxidative stress. It also protects membranes against lipid peroxidation and related effects of OS [43].

Vitamin C also protects against photoaging, UV‐induced immunosuppression, and photocarcinogens. It is available in several forms, among which l‐ascorbic acid is the most biologically active. Vitamin C inhibits tyrosinase by interacting with copper ions at its active sites, thereby reducing melanin production [44].

Vitamin C reduces UVA‐dependent melanin synthesis in G361 melanoma cells [31]. Its anti‐melanogenic effect results from its ability to scavenge reactive o‐quinones produced by interactions between tyrosinase and levodopa [45]. Additionally, vitamin C replenishes catalase activity and glutathione levels, opposing UV‐induced melanogenesis [45]. Vitamin C also reduces OS by suppressing NO production through the downregulation of eNOS and iNOS mRNA in human melanocytes, thereby mitigating the effects of NO [45]. A study on 25% l‐ascorbic acid with a chemical penetration enhancer over 4 weeks showed significant reductions in pigmentation based on MASI scores [46]. Additionally, a study comparing 5% ascorbic acid to 4% HQ over 16 weeks in treatment‐resistant hyperpigmentation revealed a 93% improvement with HQ versus 62.5% with ascorbic acid [47]. These findings highlight the role of vitamin C in hyperpigmentation; however, its efficacy may be lower than that of other topical agents.

3. BM Changes

Damage to the BM is common in patients with melasma [48], and understanding changes in this layer requires the evaluation of enzymes and proteins as well as histological changes. Cadherin‐11 is pivotal in disrupting the BM in melasma [48] as it mediates calcium‐dependent cell–cell adhesion and is expressed in dermal fibroblasts and keratinocytes. Overexpression of cadherin‐11 in fibroblasts leads to the upregulation of MMPs such as MMP‐1 and MMP‐2 in fibroblasts and MMP‐9 in keratinocytes [48].

UV interaction activates MMP enzymes, called gelatinases, that degrade type IV and Type VII collagen, which are essential components of BM [49]. This disruption promotes the migration of melanocytes into the dermis [49].

Research involving 76 melasma skin specimens revealed that 3.9% of patients exhibited vacuolar degeneration of both basal cells and BM through Fontana–Masson staining [9]. Additionally, both basal and pendulous melanocytes, as well as upper dermal fibroblasts, showed a deficit in autophagy compared to unaffected skin [50]. Autophagy‐defective melanocytes lead to increased expression of proinflammatory cytokines and chemokine ligands, increasing the levels of MMPs 3 and 13 that are responsible for collagen degradation in the BM [51].

Previous studies have demonstrated the role of BM damage in melasma [51]. A histochemical and immunohistochemical study compared melasma lesions to perilesional and photoprotected nonlesional skin. Fontana–Masson staining revealed the protrusion of pigmented basal cells into the dermal layer. Additionally, periodic acid‐Schiff staining revealed BM damage in 95.5% of patients, with 83% showing positive immunohistochemistry for anti‐Type IV collagen [49]. Chronic UV exposure is associated with increased MMP‐2 and MMP‐9 expression, leading to the degradation of types IV and VI collagen, which are essential components of the BM [52]; this observation supports the findings of anti‐type IV collagen immunohistochemistry. Additionally, the release of tryptase from mast cell degradation in the dermal layer damages the BM. Tryptase activates MMP‐2, MMP‐9, and other MMPs, leading to the destruction of collagen types IV and VI [11].

The molecular changes observed in the BM are related to the pendulous melanocyte phenomenon. Disruption of the BM facilitates the descent of epidermal melanocytes and melanin into the dermal layer, contributing to persistent hyperpigmentation. Additionally, 66% of patients with melasma had pigmented basal cells protruding into the dermal layer compared with nonmelasma lesions [27].

Transdermal radiofrequency (RF) needling is a recognized adjunct treatment for melasma due to its role in repairing damaged BM. This technique transmits RF currents through needle tips, inducing directly controlled wounding to the dermal–epidermal junction and dermis, improving the impaired extracellular matrix (ECM) in melasma lesions [53]. Additionally, RF needling leads to a nonspecific reduction in p16INK4A‐positive senescent fibroblasts and stimulates Type IV collagen production in the epidermal BM, resulting in reduced epidermal pigmentation and repair of the disrupted BM [54].

4. Dermal Changes

4.1. Senescent Fibroblasts

Photoaged fibroblasts, induced by chronic UV exposure, produce melanogenic factors that regulate pigmentation [55]. They secrete senescence‐associated secretory phenotype (SASP) factors such as vascular endothelial growth factor (VEGF), SCF, MMPs, and endothelin‐1 (ET‐1) along with growth factors and pro‐inflammatory cytokines [56]. These factors induce melanocyte hyperactivity, with VEGF contributing to neovascularization and MMPs disrupting the BM by degrading collagen Types IV and V [57, 58].

The uptake of 16INK4A, a marker of cell senescence, was assessed in 38 patients with melasma, revealing that there was a high number of p16INK4A‐positive senescent cells in lesional skin in the upper dermal layer near the dermoepidermal junction [59]. This observation aligns with clinical findings and supports current treatment approaches for melasma. The use of temperature‐controlled minimally invasive RF devices showed positive clinical results. A study involving 10 patients with melasma reported a 13.7% reduction in the lesional melanin index by Week 9 of RF treatment, likely due to its antisenolytic effects on fibroblasts [60].

Meanwhile, a trial involving 25 Asian women with facial hyperpigmentation, including melasma and simple lentigos, treated participants with a Q‐switched Nd:YAG (QSNY) laser and a fractional microneedling RF device with a 300‐μm needle depth. Both treatments significantly reduced the melanin index (p = 0.039) and senescence signaling in the epidermis [54].

Another study compared the effects of fractional laser resurfacing (FLR) with dermabrasion on senescent fibroblasts in sun‐exposed and ‐protected skin using real‐time quantitative reverse transcription polymerase chain reaction (qRT‐PCR). FLR decreased the number of senescent fibroblasts in the dermis more effectively than dermabrasion (p = 0.013) [61].

The biological effects of retinoic acid (RA) are mediated through nuclear receptors, specifically RA receptors (RAR α, β, and γ) and retinoid X receptors (RXR) [62]. Activation of RAR upregulates RAR β2, which modulates the melanin synthesis pathways, contributing to the reduction of hyperpigmentation in melasma [62].

In normal nonlesional skin, timely clearance of senescent cells promotes tissue homeostasis. In contrast, lesional skin has senescent fibroblasts that express the major histocompatibility complex molecule human leukocyte antigen E (HLA‐E) [49]. This nonclassical molecule interacts with the inhibitory receptor NKG2A on NK and CD8 T cells, inhibiting the immune responses typically observed under normal conditions [58, 63].

Senescent fibroblasts also secrete VEGF and express the functional receptor VEGFR2, stimulating neovascularization [63]. The resulting nascent cells release ET‐1, which upregulates melanogenesis in melanocytes by activating the MITF‐regulated glycoprotein nonmetastatic melanoma b (GPNMB) pathway [63]. GPNMB is a structural melanosomal protein facilitating melanosome transport from melanocytes to keratinocytes.

ET‐1 also promotes UVB‐induced pigmentation by inducing the expression of tyrosinase and TYRP‐1 while increasing the expression of MITF, MCR, and endothelin‐B receptors in melanocytes [64]. Higher levels of ET‐1 and endothelin‐B have been observed in simple lentigo [65]. Immunostaining studies have confirmed increased ET‐1 expression in the basal layer of the epidermis in lesional skin compared to that in perilesional skin, highlighting the role of microvascularization in skin pigmentation [57, 65].

Senescent fibroblasts in the dermis secrete SCF and exhibit increased expression of its tyrosine kinase receptor, c‐kit, in the dermal layer [66]. SCF is a growth factor that stimulates melanocyte DNA synthesis through tyrosine kinase ligand receptor‐mediated signaling pathways and acts as a mast cell growth factor [67]. The c‐kit receptor, which is in the melanocyte cell membrane, activates the MAPK/ERK cascade, leading to the upregulation of MITF expression [68].

Notably, there is a dose‐dependent increase in c‐kit transcription and SCF levels in the epidermis after UVB exposure [69].

Immunohistochemistry and RT‐PCR studies on 60 women with melasma revealed increased SCF and c‐kit expression in the lesional dermis compared to that in the nonlesional dermis, with no significant difference in the epidermal layer [70].

In summary, prolonged UV and VL exposure leads to inflammation, fibroblast activation, upregulation of SCF in the dermis, and enhancement of melanogenesis through c‐kit receptor activation.

Senolytics specifically eliminate senescent cells and SASPs while sparing non‐senescent cells. Senescent cells contribute to skin functional decline through SASPs, including interleukin 6, chemokine ligands (CCL) 5 and 7, SCF, and the CXC motif chemokine ligand 12 [71]. A recent study evaluated the efficacy of ABT‐263 (Navitoclax) and ABT‐737 in targeting and eliminating senescent fibroblasts using UV‐induced senescent human dermal fibroblasts and a photoaging mouse model. Treatment with ABT‐263 and ABT‐737 resulted in a reduction of SASP factor expression, a decrease in MMP induction, and an increase in collagen density [72].

4.2. Solar Elastosis

Solar elastosis, a component of photoaging, involves the accumulation of abnormally elastic tissue in the dermis due to prolonged sun exposure, with chronic UV and artificial light exposure implicated in its development [73]. The severity of solar elastosis in patients with melasma varies. Histological studies using the Verhoeff‐Van‐Gieson stain in melasma‐affected skin have shown thick, curled, and fragmented elastic fibers, consistent with the abnormal elastic tissue associated with melasma [15, 74].

UVB irradiation causes the secretion of SCF, ET‐1, iNOS, ACTH, alpha‐MSH, basic fibroblast growth factor (bFGF), and prostaglandin E2 that promote the induction of melanocyte proliferation and melanogenesis [73].

Solar elastosis resulting from UV exposure decreases the number of fibroblasts in the dermal layer and reduces collagen synthesis and UV‐induced collagen degradation, contributing to the thinning of the dermal layer and destruction of the elastin network [75]. Reduced elastin synthesis leads to increased degradation of elastic fibers and deposition of elastotic material in the dermis [76]. A study on Mexican patients with melasma found that 83% of lesional skin exhibited histological changes consistent with solar elastosis versus 29% of perilesional skin (p < 0.05) [75].

A histochemical study analyzed skin samples from 27 patients with lesional and nonlesional facial melasma, revealing a higher abundance of elastotic material in lesional skin compared to nonlesional skin (13.3% ± 2.8% vs. 10.2% ± 2.9%, p < 0.001) [77].

Microneedling RF reduces levels of promelanogenic paracrine factors, such as SCF, c‐kit, and ET‐1, and downregulates melanogenesis, potentially reversing solar elastosis through neocollagenesis that may decrease melanogenesis [78].

Topical RA effectively treats hyperpigmentation disorders [79]. There are significant improvements in melasma‐affected skin with consistent RA use, particularly in the epidermal layer (p = 0.0006) [79]. RA, which is a transretinoic acid, inhibits tyrosinase activity, reduces melanin transfer, and accelerates keratinocyte turnover. As an adjunct, it enhances skin permeation through the stratum corneum, thus targeting solar elastosis and senescent fibroblasts. However, a minimum treatment duration of 24 weeks is required to achieve optimal results [79].

4.3. Mast Cells

The presence of mast cells in human skin is influenced by intrinsic factors, including mechanisms that regulate c‐kit expression, and extrinsic factors, which are primarily associated with chronic UV exposure [80].

The number of dermal mast cells in lesional melasma skin was significantly higher than in perilesional skin. A study on 27 patients reported an increase in elastotic material in lesional skin (p < 0.0001; 13.3% ± 2.8% vs. 10.2% ± 2.9%) and mast cell presence in elastotic areas compared to nonaffected skin (p = 0.04; 173% ± 57% vs. 145% ± 57%) [77].

UV exposure increases mast cell expression, particularly in elastotic areas [81]. Mast cells influence melanogenesis through histamine release, which is upregulated following UV exposure [82]. Histamine‐2 (H2) receptors mediate the melanogenic activity of histamine via PKA activation [83].

UV exposure indirectly influences melasma by releasing mast cell tryptase and directly by damaging ECM proteins [84]. Mast cell degranulation releases tryptase and activates MMP‐9, which damages Type IV collagen in the BM [85]. Additionally, mast cells produce Granzyme B (GzmB), a serine protease that accumulates in the ECM due to chronic inflammation, including chronic UV exposure. GzmB cleaves ECM proteins directly and indirectly by releasing other proteinases. A case–control study on mice reported increased GzmB levels in mast cells following UV exposure [86].

Mast cells contribute to melasma pathogenesis through vascular changes and the promotion of solar elastosis in the dermis. Through cytokines, mast cell tryptase induces elastin production in keratinocytes and fibroblasts, facilitating solar elastosis [87]. Additionally, mast cells influence vascular changes by secreting angiogenic factors such as VEGF, fibroblast growth factor 2 (FGF‐2), and transforming growth factor‐beta (TGF‐β) [88].

There is a potential link between growth differentiation factor‐15, which is a member of the angiogenic TGF‐β family, and histamine‐induced melanogenesis pathways; however, the clinical significance remains unknown [89].

These findings reinforce the evidence of damage to both the dermal layer and BM. The use of antihistamines targeting Histamine 1 and 2 (H1 and H2) receptors for facial melasma has been evaluated, and several H1‐ and H2‐receptor antagonists, such as Ketotifen and Loratadine, have been analyzed for their role in inhibiting melanogenesis, which is accomplished through the Akt/MITF and PKC‐BII signaling pathways [90, 91]. Loratadine reduces MITF and tyrosinase expression in melanocytes through these pathways [92]. Further clinical studies are needed to assess the efficacy of antihistamines in treating melasma both as an adjunct and as monotherapy [91, 92].

4.4. Vascular Changes

The interactions between the cutaneous vasculature and melanocytes have been studied, revealing increased vascularity in melasma lesional skin and VEGF as a key angiogenic factor [93]. Changes in vascularity during melasma pathogenesis are primarily driven by UV exposure and endothelial cell dysfunction.

Dermoscopic studies have revealed increased vascularity in lesional skin, characterized by distinct telangiectatic erythema [94]. This increased vascularity is evident in the number, density, and size of blood vessels in melasma lesions compared with the perilesional skin [95]. A study evaluating vascular characteristics and VEGF expression in 50 Korean women with melasma quantified erythema intensity using the a* parameter and a colorimeter. The a* values were significantly higher in lesional skin, and factor VIIIa‐related antigen staining showed an approximately 68.75% increase in the number and size of dermal vessels in lesional skin compared with perilesional skin [95].

Changes in the dermal vasculature in melasma are associated with paracrine signaling in epidermal keratinocytes, resulting in increased production of MSH, ET‐1, bFGF, and SCF and upregulation of specific receptors on melanocytes [96]. Increased numbers of blood vessels and capillaries in the dermis increase VEGF‐A expression. These vascular endothelial cells regulate melanogenesis by secreting NO and ET‐1, inhibiting clusterin, and transforming growth factor beta‐1 [97, 98]. These secreted factors create positive and negative feedback loops that influence melanogenesis.

When discussing the vascular changes in the dermal layer of patients with melasma, it is crucial to highlight the role of chronic UV exposure. UV radiation activates keratinocytes, which upregulate VEGF production through various pathways, including the independent pathway of the tumor necrosis factor‐alpha (TNF‐α) [99].

Recently identified vascular changes in melasma have led to treatments targeting this characteristic, including the use of TXA and vascular lasers [100, 101, 102]. Dermoscopy revealed hypervascular features in melasma, with patients who had visibly widened capillaries on dermoscopy responding better to antivascular treatment than those without such changes. A study evaluating the efficacy of antivascular treatments was reviewed, and treatment responses were measured using the MASI [103]. Plasmin activity increases after UV exposure, raising alpha‐MSH and arachidonic acid levels, which contribute to melasma [103, 104, 105]. By inhibiting plasmin activity, TXA reduces hyperpigmentation and decreases VEGF and ET‐1‐induced angiogenesis [103, 106, 107]. Fontana–Masson staining techniques showed that both treatments reduced epidermal pigmentation and decreased mast cell count and vascularity [104].

Laser and light therapies, including intense pulsed light (IPL), low‐fluence Q‐switched lasers, and nonablative fractional lasers (NAFL), are treatments for managing melasma [101]. IPL improves melasma vascularity by targeting and destroying blood vessels with the chromophore oxyhemoglobin [101, 108]. IPL therapy is often used in conjunction with traditional topical treatments such as HQ. An RCT evaluated the efficacy of 4% HQ alone versus 4% HQ combined with four IPL sessions over 16 weeks, which revealed that patients receiving HQ plus IPL experienced a 39.8% reduction in the relative melanin index versus 11.6% with HQ alone [108].

Laser and light therapy can be considered for melasma that is refractory to first‐line topical treatments or chemical peels [109, 110]. NAFL has been reported to cause the longest delay in melasma relapse, whereas Q‐switched lasers have the highest relapse rates [109]. Vascular and FL therapies not only target the vascular component of melasma but also address damage to the BM layer and senescent fibroblasts [109].

5. Role of Visible Light (VL) in Melasma

Melasma pigmentation is primarily attributed to UVA/UVB stimulation [6]. However, various regions of the VL spectrum, which encompass electromagnetic radiation perceived by the human eye at wavelengths of 400–700 nm, play critical roles in the pathogenesis of melasma [111].

High‐energy VL (400–470 nm) and long‐wave UVA1 (370–400 nm) are significant factors in the etiology of melasma due to their ability to penetrate deeper into the dermis. Blue (450–495 nm) and green (495–570 nm) VL contribute to hyperpigmentation disorders, particularly in higher skin types [112]. The key mechanisms include disruption of circadian rhythms, upregulation of melanogenesis, interaction with the photoreceptor opsin‐3 (OPN3), and exacerbation of photoaging [112]. High‐energy VL activates OPN3, which mediates tyrosinase expression in melanocytes [113, 114]. The resulting increase in the activity of tyrosinase is the primary mechanism through which VL irradiation induces hyperpigmentation (Figure 1) [114].

Although evidence for the role of yellow and red VL in the pathogenesis of melasma remains inconclusive, some studies have explored their impact on cellular changes. Dose‐dependent exposure to yellow light (570–590 nm) inhibited melanogenesis and induced autophagy in human epidermal melanocytes [111, 115].

Upon exposure to VL, melanocytes undergo immediate pigment darkening, persistent pigment darkening, and delayed tanning [116]. Immediate and persistent pigment darkening are linked to the oxidation of melanin precursors, leading to melanin redistribution [116]. In contrast, delayed tanning is influenced by melanogenesis. High‐energy VL generates ROS in the dermis, contributing to OS during melasma development [117]. Additionally, high‐energy VL is associated with MMP upregulation, dermal collagen degradation, and direct damage to cellular DNA [118].

Melatonin is a hormone responsible for regulating circadian rhythms and has antioxidant characteristics. Lower levels of melatonin and catalase in patients with melasma result from OS [119]. Several studies have acknowledged the use of melatonin to target VL‐related changes in melasma. Melatonin inhibits the stimulatory effects of cAMP and alpha‐MSH, disrupting the melanin production pathway [120]. Trials on melatonin for the treatment of melasma have shown benefits. Topical melatonin 5% applied twice daily for 90 days resulted in a 31% reduction in the MASI score compared to a 37% reduction with topical HQ 4% over the same period [121]. Another study demonstrated a 22% clinical improvement with the use of oral melatonin compared to a placebo. However, the results were deemed of minor significance since participants reported no improvement in their quality of life [122].

6. Role of Hormones in Melasma

The association between female sex hormones and melasma is well established. This is evidenced by the higher prevalence of melasma among women of various ethnicities who are of reproductive age, particularly in those with Fitzpatrick Skin Types III‐V [123]. Disturbances in female sex hormones stimulate melanogenesis, as observed during pregnancy, hormone replacement therapy, and the use of oral contraceptives.

The effects of estrogen and progesterone on facial melasma development are mediated by estrogen receptor alpha (Erα/ER1), estrogen receptor beta (Erβ/ER2), and progesterone receptor (PR). Estrogen enhances tyrosinase activity, leading to increased epidermal melanin deposition [124]. Oestradiol exposure upregulates tyrosinase, TYRP1, and TYRP2 by blocking PKA [125]. Additionally, melanocytes cultured with 25 nmol/L 17β‐oestradiol, a concentration similar to levels observed in pregnancy and oral contraceptive pills, showed increased melanin synthesis [126].

Melasma lesional skin shows overexpression of ERβ in the epidermis and upper dermal fibroblasts [127]. Estrogen activates ERβ on melanocytes, directly promoting melanogenesis, while estradiol exposure also activates the Wnt/β‐catenin pathway in keratinocytes, further contributing to the pathogenesis of melasma [128, 129].

Estradiol maintains hyperpigmentation by increasing the number of blood vessels, leading to ET‐1 overexpression. Activation of Erα by estradiol triggers increased levels of VEGF and proliferation of endothelial cells. Additionally, the secretome of human dermal microvascular endothelial cells promotes melanogenesis via the ET‐1/endothelin receptor pathway, which stimulates the activity of tyrosinase and TYRP2 and induces MITF phosphorylation [129].

There is no conclusive evidence linking serum hormone levels to the development of melasma, and the association between progesterone levels and melasma has been minimally investigated. Melanocytes cultured with progesterone levels similar to those in the third trimester of pregnancy (5.10⁻⁷ M) showed decreased melanocyte pigmentation [126].

7. Conclusion

Herein, we explored both traditional and established cellular mechanisms contributing to the pathogenesis of melasma, with a strong emphasis on recent findings. Intricate interactions between the epidermis, dermis, and BM highlight how these layers contribute to the overall pathogenesis of melasma, particularly in the context of new insights into the underlying biological processes. Acknowledging the updated scientific evidence regarding the roles of mast cells, vascular changes, angiogenesis, pendulous melanocytes, senescent fibroblasts, and solar elastosis has deepened our understanding of melasma. Furthermore, we revisited established mechanisms in the pathophysiology of melasma, such as the role of OS, damage to the BM, and the influences of VL and hormones, and integrated them with novel cellular mechanisms.

Therapeutic modalities targeting specific cellular pathologies and the potential for new treatments, aligned with recent findings, pave the way for improved clinical management. We acknowledge the limitations of some studies, particularly those with small sample sizes, which may limit the reliability of their results. Additionally, studies conducted in specific ethnic groups may yield different pathophysiological findings across diverse populations. Ongoing trials examining the roles of growth factors and transcription factors in melasma pathogenesis aim to deepen our understanding and facilitate further advancements in treatment. We remain optimistic about the prospects of new pathophysiological findings and treatments that will continue to manage melasma effectively.

Conflicts of Interest

The authors declare no conflicts of interest.