Markers of Systemic Metabolic Dysfunction in Vitiligo and Their Potential Role in Disease Pathogenesis: A Narrative Review

ABSTRACT

Background

Vitiligo is a chronic autoimmune disease characterized by the progressive destruction of melanocytes, resulting in depigmented skin macules. While traditionally viewed as a cutaneous disorder driven by a specific CD8⁺ T cell‐mediated interferon‐γ (IFN‐γ) signature, emerging research suggests that vitiligo may be a systemic condition linked to metabolic syndrome (MetS) and broader metabolic dysregulation.

Methods

This review synthesizes current experimental and clinical evidence regarding systemic metabolic alterations in vitiligo. We analyzed studies investigating disruptions in glucose utilization, lipid profile imbalances, and amino acid metabolism, alongside their mechanistic links to oxidative stress and immune activation.

Results

Evidence indicates that metabolic dysfunction, including aberrant glucose metabolism and lipid alterations, precedes or exacerbates immune mobilization. Key systemic factors such as advanced glycation end‐products (AGEs), proinflammatory adipokines and reduced protective factors (vitamins and small antioxidants) create a permissive environment for melanocyte apoptosis. Furthermore, some studies concerning metabolic profiling reveal that systemic biomarkers (e.g., homocysteine, total cholesterol, LDL/HDL ratio, and urinary metabolites) correlate with disease activity and treatment response.

Conclusions

Vitiligo involves a complex interplay between systemic metabolic shifts and cutaneous autoimmunity. Integrating metabolic profiling into clinical practice offers a transformative approach for identifying subclinical abnormalities, discovering biomarkers for early diagnosis, and developing personalized management strategies that address the disease beyond its dermatological manifestations.

1. Introduction

Vitiligo is an acquired skin condition characterized by the loss or dysfunction of epidermal melanocytes. While vitiligo has traditionally been estimated to affect 0.5% to 2% of the global population, recent modeling analyzes suggest a lower global lifetime prevalence of approximately 0.36% [1]. Nearly half of all cases develop before the age of 20 [2, 3]. However, vitiligo can manifest at any age and does not exhibit a significant difference in prevalence between sexes [4]. Due to the chronic and non‐resolving feature, vitiligo patients often experience a significant reduction in quality of life due to the stigma, which can severely affect social relationships [5]. Therefore, it is important to recognize that vitiligo should not be simply considered a cosmetic issue. The characteristic depigmented spots associated with vitiligo are explained by a complex interaction of multiple etiological factors, including genetics, oxidative stress, and production of inflammatory mediators, culminating in autoimmune destruction of melanocytes [6]. Despite numerous clinical and molecular studies, the exact mechanism behind dyschromia in vitiligo remains unclear. The vitiligo patch resembles a non‐healing wound; lacking pigment‐producing cells, it fails to regenerate, permanently disrupting skin homeostasis. Extensive research now indicates that depigmentation is not the sole hallmark of the disease. Instead, vitiligo pathogenesis involves a complex interplay between non‐melanocytic cutaneous cells and extracutaneous systemic factors [7, 8]. In vitiligo, defects are not limited to melanocytes but also affect other cell types in the skin [8, 9]. Keratinocytes exhibit oxidative stress, mitochondrial dysfunction, and impaired support of melanocyte survival. Additionally, fibroblasts exhibit phenotypic changes and secrete factors that inhibit pigmentation [10], reflecting a complex cellular network disruption in vitiligo [11, 12, 13, 14]. Furthermore, peripheral blood mononuclear cells (PBMCs) from these patients show functional and biochemical defects, including altered lipid membrane composition, increased Reactive Oxygen Species (ROS) production, and abnormal DNA methylation, collectively contributing to immune dysregulation and disease pathogenesis [15, 16].

The demonstration of several systemic vitiligo‐associated markers argues for a non‐organ‐restricted disease, implying that vitiligo is not just a skin manifestation (Figure 1). Moreover, among the broad spectrum of non‐cutaneous comorbidities associated with vitiligo recently reviewed [17], metabolic dysfunctions are among the most frequently reported, as evidenced by both epidemiological studies and genetic research [18]. Genetically, there is increasing recognition that vitiligo shares common risk factors with other metabolic and systemic autoimmune diseases, such as diabetes and cardiovascular disorders. Genome‐wide association studies (GWAS) have identified genetic loci overlapping vitiligo and diabetes (Type 1 and Type 2) [18]. Mendelian Randomization analyzes further demonstrate a significant causal relationship between diabetes predisposition and increased vitiligo risk [18]. Subtype analyzes confirm this association for both immune‐mediated T1D and T2D [19], which is primarily driven by metabolic mechanisms, are associated with a higher risk of vitiligo. These findings suggest the existence of shared molecular pathways between vitiligo and metabolic disorders, further supporting the role of non‐autoimmune components in vitiligo pathogenesis (Table 1).

Figure 1.

Markers of systemic alterations in subjects with vitiligo. Schematic representation of well‐documented extracutaneous anomalies, possibly implicated in the mechanism of depigmentation. Together, these systemic disturbances may trigger, intensify and perpetuate the depigmentation process in genetically predisposed individuals.

Table 1.

Summary of different pathogenetic aspects of vitiligo.

Category	Altered markers	Change	Clinical/functional Implication
Glucose metabolism	Fasting glucose Insulin, HOMA‐ IR, c‐peptide	↑	Insulin resistance, risk of T2D, Oxidative stress
	Circulating IGF‐1	↓	Reduced insulin/IGF‐1 sensitivity Impaired oxidative stress resistance
	Advanced glycation end products (AGEs)	↑	Inflammation via RAGE, ROS, mitochondrial dysfunction
Lipid metabolism	LDL cholesterol, total cholesterol	↑	Positive correlation with VIDA score, oxidative stress
	HDL cholesterol	↓	Reduced antioxidant protection
	FABP4	↑	Insulin resistance, inflammation, TRM activation, disease reactivation
	Desnutrin	↓	Mitochondrial dysfunction, hyperglycemia
Vitamins	Vitamin E	↓	Reduced repigmentation capacity, antioxidant protection, collagen synthesis
	Vitamin C
	α‐lipoic acid
	Carotenoids
	Homocysteine	↑	Melanocytes apoptosis
	Vitamin B12	↓/↑	Controversial results in terms of beneficial effects of supplementation
	Vitamin D	↓	Reduced immune regulation, activation of proinflammatory cytokines, reduced melanogenesis
Adipokines	Leptin	↑	Pro‐inflammatory, CD8 + T cell activation
	Adiponectin	↓	Reduced anti‐inflammatory activity
Hormonal markers	Neuropeptide Y (NPY)	↑	Neuroimmune crosstalk, cytokine activation
	Norepinephrine	↑	ROS generation, damaged melanocyte
	α‐MSH	↓	Reduced melanogenesis, impaired photoprotection, oxidative stress
	MCHCR1	↑	Impaired melanogenesis, autoimmunity
Oxidative stress	H2O2, ROS	↑	Mitochondrial dysfunction
	Catalase, SOD, GSH	↓/altered	Antioxidant imbalance, immune dysregulation, cell death
Microbiome	Bifidobacterium; Staphylococcus; Propionibacterium	Altered	Dysbiosis linked to IFN‐γ signature, oxidative stress
Urinary markers	Biopterin metabolism, catecholamines	Altered	Defective melanin synthesis, stress hormones

Note: The intricate pathogenic network underlying vitiligo at the cellular level leads to equally intricate phenotypic and systemic changes.

In this review, we aimed to summarize the most frequently reported markers of systemic metabolic alterations implicated in vitiligo, thereby shedding light on the broader systemic implications of the disease.

2. Systemic Markers of Metabolic Impairment in Vitiligo Patients

Increasing evidence has proven that individuals with vitiligo may have a higher prevalence of metabolic syndrome (MetS), a cluster of interrelated conditions including insulin resistance, dyslipidemia, obesity, and hypertension [20, 21, 22, 23]. Since cutaneous abnormalities are more than a simple complication associated with MetS, the intricated reciprocal relationship between MetS and skin disorders has gained interest [24, 25]. An integrated analysis of Mendelian Randomization and circulating metabolic profile to assess vitiligo risk demonstrated that the disease is associated with various metabolic abnormalities [26]. The study corroborates these findings in C57BL/6 mouse models, demonstrating that systemic metabolic shifts precede clinical onset and exacerbate autoimmune‐mediated depigmentation. Non‐targeted metabolomics analysis on the serum of vitiligo mice validated the pathway enrichment results, suggesting that the alteration in metabolic process can influence the genetic inheritance. This evidence suggests that specific metabolites are not merely biomarkers of the disease state, but potential causal drivers that create a permissive environment for melanocyte destruction. The prevalence of MetS has been correlated with disease activity and severity [27]. Recognizing metabolic dysfunction is essential for a more comprehensive clinical evaluation and for guiding targeted therapeutic strategies.

2.1. Alteration of Glucidic Metabolism

Alterations in glucose metabolism in vitiligo skin may reflect a more complex, comprehensive condition (Figure 2). Epidemiological and genetic investigations also reveal that vitiligo patients are at significantly increased risk of developing diabetes mellitus [21], a chronic condition characterized by hyperglycemia, resulting from impaired glucose uptake and utilization. Insulin resistance is characterized by compromised glucose transport and utilization. To compensate for reduced cellular responsiveness, the pancreas increases insulin secretion. However, when β‐cell activity can no longer meet this heightened demand, these compensatory mechanisms fail, leading to chronic hyperglycemia [28]. Insulin (Ins) and insulin‐like growth factor‐1 (IGF‐1) are closely related hormones that, in addition to binding their respective receptors, can also cross‐activate each other's receptors, albeit with lower affinity. These hormones operate through parallel signaling pathways; notably, an investigation of the 50 most highly regulated genes in cells exclusively expressing either insulin receptors (IR) or IGF‐1 receptors (IGF1R) failed to identify any genes that were differentially regulated by one receptor over the other [29]. Insulin resistance impacts tissues differently based on their insulin dependence and cell‐specific sensitivity. This sensitivity is primarily driven by the density of IR and IGF‐1 receptors and the cell's metabolic intensity [30, 31]. Consequently, a diminished intracellular signaling cascade can define cellular insulin resistance even without the systemic clinical markers of Metabolic Syndrome [32]. In the skin, the presence of functional IR and IGFR in keratinocytes, melanocytes, and fibroblasts highlights the vital role of Ins/IGF‐1 signaling in maintaining cutaneous biology and cellular function [33, 34]. Very recently, our group provided evidence of generalized Ins/IGF resistance in both dermal and epidermal cells, associated with exacerbated glucose uptake, oxidative stress, and paracrine release of glucose‐related by‐products [35]. Furthermore, the finding that intensified metabolic activity may trigger autoinflammation in vitiligo keratinocytes supports the concept of a metabolic imprint in the inflammatory processes underlying the disease [35]. Reduced circulating desnutrin, alongside elevated glucose and insulin, supports the role of subclinical insulin resistance in vitiligo onset [36]. Studies consistently report higher fasting glucose, insulin, C‐peptide, and Homeostatic Model Assessment of Insulin Resistance (HOMA‐IR) levels in vitiligo patients compared to controls, suggesting a potential link to diabetes [37, 38]. Furthermore, oxidative stress and persistent inflammation are implicated in the pathogenesis of both metabolic syndrome and vitiligo, collectively disrupting cellular metabolism and exacerbating insulin resistance [21, 22, 39, 40, 41]. Specifically, inflammasome activation leads to decreased protein synthesis and mitochondrial dysfunction, partly driven by mitochondrial reactive ROS production, which contributes to the impaired function of vitiligo cells. On the other hand, mitochondrial regulation has emerged as a key axis in controlling inflammasome activity [42]. Since insulin and IGF‐1 coordinately regulate metabolic activity and share structural similarities, both IGF‐1 resistance [43, 44] and deficiency are predictably linked to metabolic syndrome [45]. Moreover, defective insulin and IGF‐1 signaling have also been demonstrated in Alzheimer's disease (AD) [44, 46]. Neuronal resistance to Ins/IGF‐1 has been proposed as a possible molecular link between diabetes and AD, indicating AD as “brain‐type diabetes” or type 3 diabetes [47]. In AD, fluctuations in glucose transporters, particularly GLUT1 and GLUT3, which are crucial for glucose uptake in the brain, are commonly observed and are associated with insulin resistance in the brain [48]. Attenuated insulin signaling impairs GLUT4 translocation, triggering neuroinflammation and cognitive decline as energy deficits disrupt ion gradients and neurotransmission [49, 50] In AD, this dysfunction also hinders Aβ clearance, promoting toxic deposition and neuronal death [51]. While traditionally viewed because of brain atrophy, emerging evidence suggests that hypometabolism may precede and trigger neuronal loss and clinical symptoms [51]. In vitiligo, the peculiar vitiligo hypometabolic feature is the reduced capacity to convert glucose into ATP [35]. While augmented glucose uptake and increased expression of glycolytic enzymes (e.g., Hexokinase2 (HK2), Pyruvate Dehydrogenase Kinase 1(PDK1), and Pyruvate Kinase M2 (PKM2)) partially compensate for metabolic dysfunction, defective mitochondrial oxidative phosphorylation simultaneously drives oxidative stress and cellular damage [35, 52]. This growing evidence suggests a pathogenic mechanism where immune mobilization is secondary to chronic metabolic dysfunction. Notably, the shared neuroectodermal origin of melanocytes and neurons explains their common susceptibility to disrupted energy homeostasis and oxidative stress, linking the propensity for neurodegenerative and pigmentary disorders [53, 54, 55]. In this respect, AD and vitiligo converge in exhibiting low ATP production, albeit caused by different mechanisms: reduced glucose imports in AD and intrinsic defects in its utilization in vitiligo. A weakened Ins/IGF‐1 axis in vitiligo may be further exacerbated by insufficient production of these factors, as IGF‐1 levels have been found significantly reduced in both the skin and blood of vitiligo patients [56]. IGF‐1 supports Ins sensitivity and promotes its secretion [57, 58]. Low circulating IGF‐1 levels have also been associated with reduced insulin responsiveness, glucose intolerance, and T2D [58, 59]. Inflammatory cytokines can suppress IGF‐1 production and activity [60]. Transgenic mice overexpressing IL‐6 exhibit significantly lower IGF‐1, an effect partially reversed by anti‐IL‐6 antibodies [61]. IL‐6 decreases IGF‐1 binding protein 3 (IGFBP‐3), which accelerates IGF‐1 clearance, lowering its circulating concentrations [62]. While the exact mechanism remains unclear, IGF‐1 likely enhances insulin signaling through indirect pathways independent of its low affinity for the insulin receptor [63]. Furthermore, IGF‐1 regulates lipid metabolism by lowering circulating free fatty acids [64], thereby improving insulin sensitivity by counteracting systemic lipotoxicity [65]. Additionally, IGF‐1 exerts protective effects on mitochondria by preventing oxidative damage associated with increased metabolic activity, enhancing ATP production, and reducing intramitochondrial ROS generation [65, 66]. Furthermore, abnormally high levels of advanced glycosylation end‐products (AGEs) have been detected in the serum of vitiligo patients compared to healthy individuals [67]. In line with this, studying the metabolic profile of vitiligo cell culture, we observed a higher production level of AGEs, which corresponded to the extracellular release [35]. In vitro data pointed attention to the intense release of AGEs by vitiligo keratinocytes, suggesting that they are implicated in the pathogenic mechanisms [35]. Keratinocytes are highly metabolically active due to their rapid proliferation, supporting epidermal turnover and the synthesis of proteins and lipids for the stratum corneum. As the dominant skin cell type, they play key roles in inflammatory and autoimmune skin diseases. AGEs, formed through non‐enzymatic modification of proteins, lipids, and nucleic acids under chronic hyperglycemia, act as Damage‐Associated Molecular Patterns (DAMPs) by binding to the Receptor for Advanced Glycation Endproducts. (RAGE). This interaction induces oxidative stress and mitochondrial dysfunction [68, 69]. AGEs interact with RAGE receptors on cutaneous immune cells, triggering inflammatory pathways linked to dermatological conditions [70]. In diabetes, this interaction induces ROS formation and pro‐inflammatory cytokine activation. Specifically, RAGE⁺ T cells in type 1 diabetes exhibit a predisposed inflammatory phenotype characterized by constitutive NF‐κB and IFN‐γ signaling upon activation [71]. Given the aberrant glucose utilization in vitiligo, research indicates that in vitro, the anti‐diabetic PPARγ agonist, Pioglitazone, improves glucose metabolism and reverses metabolic abnormalities, offering a potential therapeutic strategy for underlying dysfunction. Supporting this, bioinformatic analyzes identify PPARγ signaling as one of the three primary non‐pigmentary functional changes driving vitiligo pathogenesis [72, 73]. The activity of glucose‐6‐phosphate dehydrogenase (G6PD), a housekeeping enzyme that prevents cellular damage from ROS by producing NADPH (Nicotinamide Adenosine Dinucleotide Phosphate), has been implicated in vitiligo progression since melanocytes in vitiligo patients are more sensitive to its inhibition than normal melanocytes [74, 75]. Moreover, the expression of this metabolic regulator correlates with the activation of pigmentary gene expression [76]. A study on the Gujarat population found a genetic and biochemical association between the G6PD 3'UTR rs1050757 polymorphism and vitiligo [75]. Sustaining a role for G6PD in vitiligo pathogenesis, miRNA expression profiling in whole blood and PBMC of patients identified a pattern of small RNA molecules, including miR‐1, a regulator of mitochondrial death pathway and anti‐oxidant G6PD [77]. The overall analysis of circulating and lesional miRNA profile offered an additional connection between metabolism and vitiligo [78, 79]. Specifically, prioritization score analysis showed miRNA‐155 and miRNA‐9 were directly related to the disease [80]. miRNA‐9 regulates the release of insulin in pancreatic β‐cells in rat and mouse models [81]. miRNA‐155 is implicated in insulin signaling, glucose tolerance and uptake, obesity‐related processes and in the inflammatory status of adipocytes [82, 83]. The disruption of miRNA‐regulated transcriptomics revealed three significantly upregulated miRNAs, miR‐31‐5p, miR‐31‐3p, and miR‐194‐3p, in lesional epidermis. miR‐31 is a key keratinocyte‐specific miRNA with minimal expression in other cell types. While scarcely expressed in normal skin, miR‐31 is significantly upregulated in various skin diseases, where it can either aid homeostasis or drive hyperproliferation. Its overexpression promotes keratinocyte apoptosis and NF‐κB activation, triggering inflammatory cytokine production and leukocyte recruitment. Additionally, miR‐31‐3p, found in oxidative‐stress‐induced exosomes, contributes to melanocyte death and suppresses melanogenesis by disrupting MITF signaling. It also enhances CD8 + T cell activation, likely by reducing immunosuppression and promoting T‐cell proliferation. miR‐31‐5p from stressed keratinocytes may thus mediate oxidative stress‐induced melanocyte loss in vitiligo. Additionally, this miRNA has been linked to shifts in M1/M2 macrophage polarization via AMPK/SIRT/NLRP3 signaling under ATP/ADP imbalance [84].

Figure 2.

The complexity of glucose uptake in vitiligo pathogenesis. The detrimental glucose metabolism in vitiligo cells is illustrated in the scheme, which shows intracellular glucose‐related dysfunctions affecting both epidermal and dermal cell populations. These metabolic defects create a hostile microenvironment that compromises melanocyte survival and function, thereby playing a key role in recruiting the immune system. Such impairments include reduced ATP production, altered activity of glycolytic enzymes, and mitochondrial dysfunction, which contribute to oxidative stress and inflammation, central factors in vitiligo pathogenesis. This metabolic imbalance not only weakens cell energy but also promotes an environment that facilitates immune cell activation and disease progression.

2.2. Dyslipidemia

The relationship between vitiligo and lipid imbalances has attracted growing interest in recent years. Several studies have reported a higher prevalence of obesity among individuals with vitiligo [85, 86]. Conversely, some studies found no significant link between vitiligo and anthropometric markers like BMI or waist circumference [87], necessitating further longitudinal research. However, recent work by Guanglu et al. emphasizes the role of lipids, identifying 10 lipid‐related molecules among 36 abnormal metabolites in vitiligo patients [26]. Among these, myristoleate showed the highest risk effect for vitiligo development. Another study employing untargeted metabolomics in a population of progressive vitiligo patients identified lower piperine and pantothenic acid, and upregulated 1‐stearoylglycerol, stearoyl ethanolamide, and imidazoleacetic acid, all related to the biosynthesis pathway of unsaturated fatty acids [88]. Vitiligo patients frequently exhibit elevated LDL and reduced HDL cholesterol [17, 22, 67, 88]. This dyslipidemia, alongside factors like hypertension and smoking, activates the NADPH oxidase system, inducing excessive superoxide production and oxidative stress. Notably, a positive correlation exists between the Vitiligo Disease Activity (VIDA) score and serum cholesterol, LDL levels, and the LDL/HDL ratio [89]. Consistent with these findings, HMG‐CoA reductase inhibitors like simvastatin have been reported to occasionally reverse depigmentation [90, 91]. Supporting the therapeutic potential of simvastatin, its use in vitro on human melanocyte cultures protects from oxidative stress by activating detoxifying pathways [92]. However, clinical trials investigating oral and topical administration of statins failed in significant repigmentation [93, 94]. One key finding is the increase in circulating levels of fatty acid‐binding protein 4 (FABP4) in vitiligo patients compared to matched healthy controls [95]. FABP4 is involved in insulin sensitivity, lipid metabolism, inflammation, and glucose production, linking it to states of hyperglycemia and dyslipidemia commonly observed in vitiligo cases [96]. A significant association between high FABP4 levels and MetS has been observed in vitiligo patients [97]. FABP4 has proinflammatory properties in macrophages. Furthermore, decreasing the levels or activity of FABP4 has been shown to improve metabolic health. Due to the double role in lipid metabolism and inflammation [97, 98], FABP4 might represent a bridge between the metabolic aspect and autoimmunity of vitiligo. FABP4 has been found to induce insulin resistance by increasing the intracellular lipid contents [99], and recently, abnormal high FABP4 has been observed in newly diagnosed type 1 and type 2 diabetes compared to controls [100]. Chronic activation of FABP4 under conditions of metabolic stress, such as obesity, is habitually associated with intensified lipolysis and contributes to the progression of various immunometabolic disorders [101]. Plasma levels of desnutrin, a member of the family of proteins involved in adipose tissue lipolysis, are significantly reduced in individuals with vitiligo compared to healthy controls [36]. Decreased desnutrin in subjects with vitiligo significantly correlates with fasting insulin levels, HOMA‐IR, VLDL, LDL, and fasting blood glucose, amount of serum insulin and glucose, but not with HDL, triglyceride, and cholesterol levels [36]. Desnutrin promotes mitochondrial function essential for insulin secretion by pancreatic islet cells. Experimental ablation of desnutrin in mice leads to impaired mitochondrial dynamics, characterized by hyperfused mitochondria, and results in hyperglycemia [102]. Leptin, an adipokine regulating energy homeostasis and immune function, is significantly elevated in vitiligo, where high serum levels of both leptin and resistin correlate with increased disease activity [103]. Leptin promotes melanocyte destruction by activating CD8⁺ T cells and enhancing the production of pro‐inflammatory mediators, including IFN‐γ, perforin, and granzyme B [103, 104]. Conversely, circulating levels of the protective adipokine, adiponectin, are notably reduced in these patients [103].

2.3. Hormonal Factors in Vitiligo Pathogenesis

An emerging concept suggests that vitiligo pathogenesis involves a functional interplay between the neuroendocrine and immune systems [105]. The cutaneous neuroendocrine network is crucial for skin homeostasis, including pigmentation control. Neuropeptides and hormones from peripheral nerves can interact with pro‐inflammatory cytokines, disrupting melanocyte function and survival [105]. Elevated levels of neuropeptide Y (NPY) have been consistently observed in both lesional tissue and plasma samples from patients with vitiligo, compared to healthy individuals [106, 107]. Moreover, polymorphisms in the NPY gene, specifically −399 T/C (rs16147) and +1128 T/C (rs16139), have been implicated in increased transcriptional activity and are associated with heightened susceptibility to vitiligo and the concurrent inflammatory cytokines [108, 109]. These findings highlight a potential neuroimmune mechanism contributing to melanocyte degeneration in vitiligo. Anomalous high norepinephrine (also known as noradrenaline) levels have been detected in the melanocyte microenvironment and plasma of patients with vitiligo [110]. Elevated local or systemic norepinephrine can modulate keratinocyte and immune cell activity, indirectly impairing melanocyte viability by stimulating cytokine release and immune cell recruitment [111]. These findings suggest that neuroendocrine‐immune axis dysregulation triggers or exacerbates vitiligo. Additionally, dysregulated norepinephrine is linked to hypertension and mood disorders [112]. The psychosocial burden and chronic stress of visible lesions further elevate anxiety and depression [113, 114], creating a self‐sustaining loop that drives disease progression. Corticotropin hormone in the skin upregulates the synthesis and secretion of proopiomelanocortin and its derived peptides, with POMC being an important regulator of melanogenesis [115]. The expression of POMC and its receptors, melanocortin receptor‐1 (MC1R) and −4 (MC4R), is significantly decreased in lesional vitiligo skin, but increased in non‐lesional vitiligo skin [116]. Notably, α‐MSH levels are significantly reduced in both the epidermis and blood of patients with vitiligo [117, 118]. Based on this observation, the use of Afamelanotide, an α‐MSH synthetic analog, in combination with phototherapy has been proposed as a potential treatment option [119]. Beyond its well‐known role in regulating pigmentation, α‐MSH also exerts multiple effects in the skin, including protection against oxidative stress, anti‐inflammatory and anti‐fibrotic actions [120, 121, 122]. The melanin‐concentrating hormone receptor 1 (MCHR1), identified as an autoantigen in vitiligo, also links vitiligo to diabetes. Function‐blocking antibodies against MCHR1, produced by B cells, have been found in vitiligo patients [123, 124] and individuals with diabetes [125]. This autoantigen is of particular interest because it is the only known cell surface antigen identified in vitiligo. The ligand melanin‐concentrating hormone (MCH) is a hypothalamic neuropeptide that regulates food intake and energy balance, partly by stimulating insulin secretion [126]. It is plausible that MCHR1 antibodies in vitiligo patients exert a non‐physiological stimulatory effect on pancreatic islet cells, leading to systemic metabolic implications. In melanocytes, MCH acts as an antagonist of α‐MSH, which is the primary regulator of melanogenesis [127]. In vitro stimulation of human melanocytes with MCH leads to a pronounced reduction in melanogenic activity [127]. Moreover, MCH mRNA expression is upregulated in both lesional and non‐lesional skin of vitiligo patients compared to healthy controls.

2.4. Micronutrients

Increasing attention has focused on nutritional factors, particularly vitamins, in vitiligo pathogenesis. Studies suggest that deficiencies or supplementation may influence progression and repigmentation via antioxidant, immunomodulatory, and melanocyte‐supporting effects. While definitive conclusions are lacking, antioxidant micronutrients may primarily act by increasing the minimal erythema dose (MED), thereby enhancing phototherapy efficacy by shielding melanocytes from oxidative and immune damage [128]. The imbalances in serum levels of antioxidants, such as selenium, copper, and zinc, have been associated with increased vitiligo risk, suggesting that nutritional deficiencies may contribute to melanocyte degeneration [129, 130]. Vitamin C, a potent antioxidant often deficient in vitiligo patients, may aid pigmentation by preventing oxidative damage, supporting collagen synthesis, and promoting melanin production. However, clinical evidence for its effectiveness as a standalone treatment is limited, with most studies focusing on its use alongside other antioxidants [131]. Vitamin D plays a multifaceted role in skin homeostasis, immune regulation, and melanocyte biology. Through the Vitamin D receptor (VDR), it promotes melanogenesis and protects melanocytes from apoptosis by inhibiting pro‐inflammatory cytokines [132]. Although serum levels are frequently lower in vitiligo patients, particularly those with limited sun exposure, findings vary by geography, environment, and ethnicity [133]. Notably, topical analogs like calcipotriol and tacalcitol have shown efficacy in repigmentation, especially when combined with narrowband UVB or topical corticosteroids [134]. However, genetic studies examining VDR polymorphisms have revealed inconsistent associations with vitiligo susceptibility across different ethnic populations [135, 136]. Animal studies with diets enriched in vitamins and antioxidants, including green tea polyphenols, suggest these may aid repigmentation by reducing cellular oxidative stress. However, polyphenol effects may be limited to the epidermis due to poor systemic absorption [137, 138]. Oral vitamin E, often administered in combination with other antioxidants such as α‐lipoic acid, vitamin C, carotenoids, and fruit extracts, has shown some promise in promoting repigmentation; however, the independent effect of single factors remains unclear [139, 140]. Research on vitamin B12 has yielded mixed results. While some uncontrolled studies report halted disease progression and partial repigmentation, controlled clinical trials have not confirmed significant therapeutic benefits [141]. While vitamins D and E may be useful adjuncts, particularly with phototherapy or immunomodulators, current evidence is insufficient to support their routine use, highlighting the need for well‐designed trials to establish optimal dosages, combinations, and strategies.

2.5. Disturbance of the Physiological Oxidative‐Reductive Equilibrium in Vitiligo

Although the local oxidative imbalance in the skin microenvironment has been widely studied, cumulative research indicates that oxidative stress is present not only in lesional skin but also in the systemic circulation of patients with vitiligo [74]. Elevated levels of ROS and reduced levels of antioxidants have been detected in the peripheral blood of vitiligo individuals, suggesting a pro‐oxidant state at the systemic level [142]. Furthermore, some studies have reported correlations between the degree of oxidative stress in the blood and disease activity or progression, suggesting these markers could be useful for monitoring disease status or therapeutic response [143]. This systemic oxidative milieu could potentially amplify melanocyte‐specific autoimmunity by promoting antigen presentation, T‐cell activation, and the release of inflammatory cytokines [144]. Oxidative stress plays a central role in the development of both vitiligo and MetS [145]. This is particularly important because oxidative stress can lead to the activation of inflammatory pathways that impair cellular functions. Some studies report elevated levels of both oxidants and antioxidants, while others find no difference, or even lower levels of these parameters in vitiligo patients compared to controls. Individual antioxidant levels, particularly for Superoxide Dismutase (SOD) and catalase, have been extensively studied in vitiligo, but data on total antioxidant capacity are scarce. Some studies report significantly higher levels of SOD [146, 147, 148, 149], while others, including our recent report, detected lower activity in vitiligo patients [67, 150, 151]. The increased ROS levels, by altering the structure of lineage‐specific proteins such as tyrosinase and Melanoma Antigen Recognized by T cells 1 (MELAN‐A), may lead to the formation of new epitopes, triggering an autoimmune response. Increased markers of oxidative stress in the early stages of vitiligo, along with elevated levels of autoantibodies in the advanced stages, suggest that oxidative stress plays a role in the initiation of vitiligo pathophysiology [152]. Elevated levels of homocysteine, an amino acid metabolite, have been identified as a circulating marker of oxidative stress and a risk factor for vitiligo [153, 154]. Dysregulation in homocysteine metabolism in vitiligo may further contribute to the disease's pathogenesis. Homocysteine induces melanocyte apoptosis by activating ROS and the endoplasmic reticulum (ER) stress pathway [155]. Moreover, homocysteine has been shown to disrupt melanogenesis; however, this defect can be reversed through folic acid supplementation, which restores normal melanocyte function [155]. Recent studies evaluating cysteine, a downstream product of homocysteine metabolism, have revealed reduced levels in patients with vitiligo, confirming impaired homocysteine metabolism [67, 156]. The imbalance in oxidative stress also affects lipid metabolism, as seen in the alteration of fatty acid (FA) pathways in vitiligo patients, which shows a shift toward pro‐inflammatory n‐6 fatty acids [157]. Oxidative stress is closely linked to mitochondrial dysfunction, which in vitiligo patients manifests as abnormal glucose metabolism and increased ROS production [52, 72, 158, 159]. In mitochondria, ROS are generated as by‐products during the biosynthesis of adenosine triphosphate (ATP), making mitochondria a primary source of cellular ROS. At the cellular level, melanin synthesis itself represents a significant source of intracellular oxidative stress, as it generates ROS during its biosynthetic pathway [160]. Melanin plays a dual role: on one hand, it protects against UV‐induced DNA damage; on the other, the melanogenesis process itself generates ROS [161]. While eumelanin offers more protection against oxidative stress and correlates inversely with basal ROS levels, pheomelanin exerts an intrinsic phototoxic/pro‐oxidant role associated with increased oxidative DNA and lipid damage [162]. Excess ROS can impair dendrite formation in melanocytes, weaken their adhesion to the basal layer of the epidermis, and ultimately lead to melanocyte detachment [163]. This detachment facilitates melanocyte migration and may act as a trigger factor for the activation of immune responses in the skin [163].

2.6. Altered Immunometabolism in Vitiligo

The function of immune cells largely depends on their metabolic activities, which are deeply influenced by intrinsic characteristics and the metabolic dialog with the microenvironment. Collectively, metabolic regulation of immune function is indicated as “immunometabolism”. In the case of inflammatory stimuli, the primary alteration in bioenergetic metabolism involves promoting glycolysis over oxidative phosphorylation [164]. Altered metabolic pathways in immune cells promote inflammation and sustain the disease's chronicity, linking metabolism closely with immune dysregulation in vitiligo. Thus, immunometabolism is emerging as a promising area of research in the pathogenesis of vitiligo. Studies suggest that mitochondrial dysfunction, increased oxidative stress, and defects in specific metabolic pathways contribute to the dysregulation of both innate and adaptive immune responses in vitiligo [165]. Skin aberrant activation of innate immune cells includes inflammatory dendritic cells, which secrete pro‐inflammatory cytokines and present melanocyte‐derived antigens to T cells, thereby activating them. These autoreactive T cells then directly target and destroy melanocytes [166]. Abnormal lipid metabolism significantly impacts T cell dysfunction in vitiligo. Skin tissue‐resident memory T cells (TRM) possess a unique metabolic profile characterized by increased mitochondrial mass and fatty acid beta‐oxidation (FAO) to ensure longevity and rapid recall [167]. In vitiligo, autoreactive CD8⁺ TRM cells release IFN‐γ, promoting melanocyte destruction and recruiting additional cytotoxic cells [168]. In vitro studies highlight the overexpression of FABP4 in these autoreactive populations [169], suggesting it promotes immune‐mediated mechanisms beyond lipid transport, such as endothelial activation and inflammatory cytokine upregulation [170]. Because TRM cells depend on exogenous free fatty acids (FFAs) for skin residency, targeting these metabolic pathways, for instance, using trimetazidine to block mitochondrial FAO, can reduce their lifespan [171, 172]. Clinically, lipid‐lowering agents like statins may reduce disease activity, offering a potential therapeutic avenue beyond their cardiovascular benefits [173]. Statins (HMG‐CoA reductase inhibitors), commonly used to manage hyperlipidemia, have been incidentally associated with vitiligo regression in some clinical observations [174]. A particularly noteworthy observation is that statins may exert anti‐inflammatory effects by targeting memory T cells, reducing their numbers, and limiting their cytokine production at sites of inflammation [174]. Furthermore, in vitro experiments have shown that statins inhibit the proliferation and cytotoxic activity of melanocyte‐specific CD8⁺ T cells. In a mouse model of vitiligo, simvastatin was able to both prevent and reverse depigmentation by interfering with IFN‐γ signaling [90]. Alteration of the antioxidant patterns described in melanocytes has also been demonstrated in PBMC of patients in the active phase of the disease, indicating susceptibility to oxidative stress of immune cells [175, 176]. Accordingly, PBMC in active vitiligo patients present compromised mitochondrial membrane potential and the tendency to accumulate intracellular ROS [175]. The precarious redox balance is implicated also in the regulation of regulatory T cells (Tregs), a population of immune cells having a suppressive function against CD4+ and CD8+ cells. The relative amount of Tregs resulted lower in lesional, peri‐lesional and normally pigmented vitiligo skin compared to healthy controls [177, 178] with a significant difference between active and stable disease [179], indicating a central role in the disruption of self‐immune tolerance in vitiligo. Independent of the amount, vitiligo Tregs demonstrated defects in secreting immunosuppressive cytokines, a deficiency that could be restored normalizing the expression of heme oxygenase1 (HO‐1) [179].

2.7. Possible Role of Dysbiosis in Vitiligo

The skin microbiome comprises a heterogeneous microbial community of beneficial microorganisms that undergo continuous dynamic changes influenced by host‐related factors, such as sex, age, skin pH, sebum composition, and anatomical variations, as well as environmental agents including UV radiation, climate, nutrient availability (dependent on diet and metabolism), moisture, and pollution [180]. The initial alteration in the skin microbiome typically occurs during pathogenic invasion. Viruses, bacteria, and fungi can colonize the skin, displacing commensal microorganisms. This results in skin barrier disruption, toxin release, and a pronounced inflammatory response [181]. Microbial imbalance, generally referred to as dysbiosis, has been implicated in several dermatological conditions, including atopic dermatitis, acne, psoriasis, rosacea, eczema, vitiligo, alopecia areata, chronic wounds, and skin cancers [182, 183, 184]. In vitiligo, dysbiosis has been investigated both at the skin and gut levels. A recent systematic review of six studies identifies a reduction in gut bacterial diversity associated with systemic dysbiosis. Conversely, skin microbiome findings remain heterogeneous and occasionally conflicting, often due to varying sampling methods between lesional and healthy sites. While microbial alterations are evident, the authors conclude that small sample sizes necessitate larger cohorts to confirm a definitive pathogenic role in vitiligo [185]. The observation of increased abundance of bacterial genes involved in mucus degradation suggested a potential compromise of the intestinal mucus barrier in vitiligo. Functional analyzes also identified a higher abundance of genes related to fatty acid and lipid metabolism in vitiligo patients. The richness and distribution of bacterial species found in the stool of vitiligo patients resembled profiles previously reported in autoimmune skin conditions such as scleroderma and psoriasis, and more broadly, in systemic autoimmune diseases including type 1 diabetes, Graves' disease, lupus, and multiple sclerosis [186]. In 2016, Ganju et al. were the first to demonstrate dysbiosis in the microbial community structure of vitiligo, revealing significant differences in microbial diversity between lesional and matched non‐lesional skin [187]. Subsequent studies extended the characterization of disease‐specific microbial profiles to the gut microbiome as well [188]. More recently, a comprehensive investigation compared both gut and skin microbiomes in vitiligo patients and healthy controls. The findings revealed that vitiligo patients shared similar microbial compositions across skin and gut sites, distinctly different from those of healthy individuals, suggesting the existence of a gut–skin axis in vitiligo [189]. In this study, the use of both swab and excision biopsy sampling allowed a detailed comparison between patients and controls. Notable differences were observed in tissue biopsies between vitiligo patients and healthy subjects, while no significant variation emerged between lesional and non‐lesional skin in vitiligo patients. A unique feature identified in some vitiligo subjects was the near‐complete absence of Bifidobacterium in the skin microbiota, an organism known for its protective effects against innate immune activation [190]. These individuals also exhibited elevated levels of circulating IFN‐γ, CXCL9, and the stress marker CXCL16. This immune signature was associated with the presence of human mitochondrial DNA (mtDNA) fragments, suggesting mitochondrial damage as a potential trigger for microbial alterations [190]. Dou et al. further confirmed reduced gut microbial diversity in vitiligo patients and identified Bacteroides and Parabacteroides as disease‐specific microbial markers. These taxes were significantly associated with the Vitiligo Area Scoring Index (VASI) and disease duration [191]. Notably, narrowband UVB phototherapy has been shown to modulate the cutaneous microbiota in vitiligo patients, potentially counteracting dysbiosis and contributing to therapeutic effects [192]. Skin microbiota differences between active and stable vitiligo have been explored to elucidate mechanisms of disease progression [193]. Active vitiligo is characterized by significantly reduced microbial diversity in both lesional and non‐lesional skin compared to stable patients and healthy controls, indicating systemic dysbiosis [194]. This state is associated with an increased abundance of potentially pathogenic taxa, such as Staphylococcus and Propionibacterium, which are linked to cutaneous inflammation [181, 194]. In contrast, stable vitiligo exhibits a more balanced microbiome, with higher levels of commensal bacteria like Corynebacterium, closely resembling healthy skin [194]. These findings suggest that microbial dysbiosis correlates with disease activity and a pro‐inflammatory environment. Consequently, restoring a healthy skin microbiome represents a promising therapeutic strategy, while the microbiota itself holds potential as a biomarker for monitoring disease activity and treatment response [195]. Parallel analyzes of the gut microbiome and patient serum metabolome have revealed correlations with specific metabolites, including taurine, uridine, and nicotinamide, suggesting a relationship between substrate availability and microbial colonization [188]. Insights into microbiome‐associated metabolism have also provided relevant information. Metagenomic analysis of the vitiligo microbiome has identified several interconnected microbial metabolic pathways potentially implicated in disease pathogenesis. Increased galactose degradation has garnered attention, as galactose fermentation produces pyruvate, which can be further converted to acetyl‐CoA, both of which may promote oxidative stress [195]. Additionally, biochemical predictions indicate reduced cysteine degradation in the vitiligo microbiome. This potentially reflects altered metabolism in both the microbiota and the host, as elevated serum homocysteine, a cysteine precursor, is characteristic of vitiligo patients [67, 196]. These findings highlight a complex interplay between microbiome composition, microbial metabolism, and host biochemical pathways. It is hypothesized that such microbial imbalances could exacerbate mitochondrial dysfunction by increasing oxidative stress or disrupting mitochondrial dynamics [165]. An intriguing aspect consists of the demonstration that some bacterial proteins have mitochondrial targeting sequences and thus a propensity to be translocated into host mitochondria [197]. Emerging evidence suggests that restoring a healthy skin microbiome, through interventions such as probiotics or prebiotics, may modulate immune responses and enhance mitochondrial function, offering a potential adjunct to conventional immune‐modulating therapies [198]. At the intestinal level, the crosstalk between host and microbiota plays a key role in regulating mitochondrial activity and ROS production [198]. Despite its relevance, the skin mycobiome remains under‐investigated. Kuroda et al. reported slightly higher α‐diversity of fungal flora in vitiligo patients [199]. Alterations in the fungal repertoire may be particularly significant as certain species, such as those in the order Capnodiales, produce melanin and related pigments [200]. These fungal‐derived molecules are structurally like human melanocyte antigens and may act as molecular mimics, potentially triggering host autoimmune responses.

2.8. Urinary Metabolomic and Proteomic Profiling in Vitiligo

Despite being a useful, non‐invasive, and rapid approach to characterize urinary metabolite patterns associated with pathological conditions; few studies have explored urinary profiling in vitiligo. Previous research has mainly focused on specific metabolites, such as circulating and urinary catecholamines and vanillylmandelic acid [201, 202], with no comprehensive urinary metabolomic investigation available to date. Notably, norepinephrine, epinephrine, and metanephrine are significantly associated with progressive or recent‐onset disease [203]. Qian and colleagues conducted an untargeted urinary metabolomic analysis that identified 71 metabolites distinguishing vitiligo patients from healthy controls [204]. Significant pathway enrichment was observed in cytochrome P450 drug metabolism, biopterin metabolism, vitamin B9 (folate) metabolism, selenoamino acid metabolism, and methionine and cysteine metabolism [205]. Defects in biopterin synthesis and regulation are key contributors to vitiligo pathogenesis. H₂O₂ oxidizes (6 R)‐l‐erythro‐5,6,7,8‐tetrahydrobiopterin to cytotoxic 6‐biopterin, damaging melanocytes in vitro. Low activity of 4a‐hydroxy‐tetrahydrobiopterin dehydratase leads to accumulation of 7‐tetrahydrobiopterin, which inhibits epidermal phenylalanine hydroxylase and disrupts melanin synthesis, contributing to depigmentation [206]. Notably, the alkaloid biosynthesis pathway correlated with disease activity; for example, (S)−3‐hydroxy‐N‐methylcoclaurine, an isoquinoline alkaloid intermediate, was elevated during effective treatment compared to the active phase [207]. These findings, along with identified steroid hormone‐related metabolites, suggest potential for treatment monitoring, though further validation is required. These included dehydroepiandrosterone (DHEA), cortexolone, and 4‐methoxy‐17β‐estradiol. DHEA, a stress‐related hormone, increased with treatment, consistent with Gurpinar et al. [208], who found that low DHEAS levels may predict poor treatment response. Cortisol, associated with stress and depression in vitiligo, decreased during treatment, indicating its link to the active disease stage [209]. 4‐methoxy‐17β‐estradiol also increased with clinical improvement, possibly due to its effect on tyrosinase activity in melanocytes. These findings highlight the complex interplay of neurological, psychological, and endocrine disturbances in vitiligo. Furthermore, a urinary proteomic study of 58 patients with advanced non‐segmental vitiligo revealed 242 differentially expressed proteins before steroid treatment, with RBP‐1 and TOR1AIP‐1 proposed as biomarkers of glucocorticoid (GC) efficacy [207]. These studies encourage the consideration of metabolomic and proteomic urinary profiles as promising tools for early diagnosis, treatment monitoring, and prediction of disease progression [205, 209].

3. Conclusions

While vitiligo is primarily known for its visible depigmentation, emerging clinical evidence (listed in Supplementary Table 1), highlights a complex interplay between metabolic dysfunction, immune alterations, nutritional factors, and microbial imbalance in the pathogenesis of vitiligo. Although the relationship between vitiligo and insulin resistance, dyslipidemia, and obesity is still unclear, these conditions share underlying mechanisms like oxidative stress and inflammation. These local microenvironmental factors are potentially determinative in predisposing the skin to autoimmune activation. A critical element involves the interplay between systemic metabolic deficiencies and local triggers, including mechanical stress chemical insults, and UV exposure. These synergistic interactions may lower the threshold for immune dysregulation and the subsequent onset of autoimmunity. Skin and gut dysbiosis, through the gut‐skin axis, play key roles in immune regulation and melanocyte survival, and microbiome modulation may complement existing treatments. Also, vitamins D and E represent promising complementary nutritional interventions, but robust clinical evidence is lacking. Currently, no metabolic or microbial marker has been sufficiently validated for routine clinical use to predict disease course or to predict treatment response. So far, an integrated multi‐omic approach is needed to improve understanding and treatment of vitiligo, with further large‐scale studies required to develop effective targeted therapies.

Author Contributions

Federica Papaccio: conceptualization, investigation, writing – original draft, writing – review and editing, data curation. Simona Scano: conceptualization, investigation, writing – original draft, writing – review and editing, data curation. Barbara Bellei: conceptualization, investigation, writing – original draft, writing – review and editing, data curation, supervision.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

Barbara Bellei, as author guarantor affirms that this manuscript is an honest, accurate, and transparent account of the study being reported and no important aspects of the study have been omitted and any discrepancies from the study as planned.

Supporting information

Supporting File

Papaccio F., Scano S., and Bellei B., “Markers of Systemic Metabolic Dysfunction in Vitiligo and Their Potential Role in Disease Pathogenesis: A Narrative Review,” Health Science Reports 9 (2026): e72950, 10.1002/hsr2.72950.

Data Availability Statement

The authors have nothing to report.