Metabolic syndrome and dermatological diseases: association and treatment

Abstract

Metabolic syndrome (MetS) is a clinical syndrome associated with cardiovascular disease, diabetes, obesity, and dyslipidemia. Its primary features include dyslipidemia, hypertension, abdominal obesity, and insulin resistance (IR). Recently, research has revealed that MetS is not only a manifestation of internal metabolic disturbances but is also closely associated with various dermatological conditions, including inflammatory skin diseases, autoimmune skin diseases, and skin tumors. These studies have clarified the complex mechanisms underlying the interaction between MetS and these skin diseases, including IR, chronic inflammatory responses, and oxidative stress. This review summarizes the association between MetS and related dermatological conditions and their shared physiological mechanisms. It aims to provide clinicians with new therapeutic strategies and preventive measures to improve the treatment outcomes and quality of life of patients with skin conditions.

Introduction

Metabolic syndrome (MetS) is a cluster of interrelated risk factors for cardiovascular disease (CVD), diabetes mellitus (DM), obesity, and dyslipidemia. Typically, these include hypertension, central obesity, abnormal cholesterol levels, and insulin resistance (IR). Genetic and environmental factors influence this syndrome and are closely associated with systemic organ damage. The diagnostic criteria for this syndrome are as follows: Central obesity (Asian adults: Male waist circumference ≥ 90 cm or female waist circumference ≥ 80 cm; European adults: Male waist circumference ≥ 94 cm or female waist circumference ≥ 80 cm), low-density lipoprotein (LDL; < 1.03 mmol/L for males, < 1.29 mmol/L for females), elevated triglycerides (TG; > 1.69 mmol/L or previously treated for dyslipidemia), elevated blood pressure (> 130/85 mmHg), and fasting glucose ≥ 5.6 mmol/L or receiving related treatment. A diagnosis is confirmed if a patient meets three or more of these criteria. This syndrome constitutes a significant global public health challenge, imposing substantial burdens on individual health and health care systems.

IR, dyslipidemia, elevated pro-inflammatory cytokines, and decreased levels of anti-inflammatory cytokines, including adiponectin, oxidative stress, and factors linked to gut microbiota and intestinal health, are implicated in MetS development. MetS is closely associated with various dermatological conditions. Physiological and metabolic abnormalities associated with MetS can directly or indirectly affect skin health. For instance, IR and hyperglycemic environments may lead to abnormal epidermal cell proliferation and differentiation, contributing to the development of dermatoses. Moreover, chronic inflammatory states in MetS may exacerbate or trigger inflammatory skin disorders, including psoriasis. Furthermore, obesity-related skin friction and increased pressure may induce cutaneous manifestations.

This study aimed to improve the understanding of the interaction between these two diseases and investigate potential prevention and treatment strategies through a comprehensive review and analysis of the existing literature. Additionally, it discussed the effective clinical management strategies for MetS to minimize its negative impact on skin health. By providing valuable information, this study seeks to help clinicians make informed decisions when treating patients with concurrent skin diseases and MetS while also guiding future research.

MetS-related cutaneous disorders

Erythematous papulosquamous skin disease

Psoriasis

Psoriasis is a complex, multisystemic inflammatory disease. Extensive research has demonstrated a significant association between psoriasis and MetS (odds ratio [OR]: 2.89, 95% confidence interval [CI]: 2.2–3.80), which has been confirmed across diverse populations globally[1]. Paschoal et al.[2] reported that the prevalence of MetS among patients with psoriasis was 43.3%. Moreover, Kim et al.[3] reported a higher prevalence of psoriasis among Korean adults with MetS. They found that the risk of psoriasis increased with an increase in the number of risk factors for MetS. Gisondi et al.[4] emphasized that the MetS incidence was high among female patients with psoriasis aged ≥ 40 years. These findings underscore the importance of monitoring metabolic health in patients with psoriasis, particularly when psoriasis area and severity index (PASI) scores increase [5]. Among the various components of MetS, patients with psoriasis have the highest prevalence of obesity and diabetes [6–8]. For instance, Kokpol et al. conducted a study in Ireland and reported that the MetS prevalence was higher among patients with psoriasis than among the general population (49.25% versus 30.65%). These associations were particularly significant in terms of hyperglycemia, hypertension, and abdominal obesity [9]. Henseler et al. demonstrated significantly higher rates of diabetes and obesity among patients with psoriasis than among controls [10]. Furthermore, most cross-sectional studies found abnormalities in the lipid profiles of patients with psoriasis [11, 12]. However, this finding is inconsistent among all studies.

Research on the mechanisms underlying the association between psoriasis and MetS has revealed a complex interplay of factors. Psoriasis is a chronic inflammatory skin disease driven by mechanisms that involve Th17 cells and their cytokines, including interleukin (IL)-17, tumor necrosis factor-alpha (TNF-α), and IL-22 (Table 1) [13]. These factors contribute to abnormal differentiation, excessive keratinocyte proliferation, and symptom exacerbation. Inflammatory cytokines, particularly IL-17, have been implicated in MetS pathogenesis, leading to vascular inflammation and dysfunction (Fig. 1) [14].

Table 1.

Inflammatory makers in MeTS and skin-related conditions

Metabolic syndrome	IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, G-CSF, TNF-α, VEGF, PDGF-BB, GM-CSF, RANTES
Psoriasis	IL-1, IL-2, IL-6, IL-12, IL-15, IL-22, IL-23, IFN-γ, TNF-α
Lichen planus	IP-10, MCP-1, RANTES, MIG
Atopic dermatitis	IL-3,IL-4, IL-5, IL-12, IL-13, IL-16
Androgenetic alopecia	IL-1,TNF-α
Alopecia areata	IFN-γ, TNF-α, IL-2, IL-15
Systemic lupus erythematosus	IL-17, IL-23, TNF-α
Behçet’s syndrome	IL-1, IL-6, IL-8, TNF-α
bullous pemphigoid	IL-17
Vitiligo	TNF-α, IL-1, and IL-6, C-reactive protein (CRP), and homocysteine, IFN-γ

IL, interleukin; G-CSF, granulocyte-colony stimulating factor; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; PDGF-BB BB, isoform of the platelet derived growth factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; RANTES, regulated on activation, normal T cell expressed and secreted (chemokine, also known as CCL-5); IFN-γ, interferon-γ; IP-10, interferon gamma-induced protein 10; MCP-1, monocyte chemoattractant protein 1; MIG, monokine induced by gamma interferon

Fig. 1.

The interactions between chronic inflammatory pathways, MetS, and various skin diseases. These interactions are primarily influenced by dietary habits, immune responses, IR, and metabolic complications. High consumption of sugar, carbohydrates, and dairy activates the PI3K/AKT and mTORC1 pathways, leading to gut microbiota dysbiosis, particularly affecting Akkermansia muciniphila. Th17 and Th1 cell activation increases the secretion of pro-inflammatory cytokines (TNF-α, IL-22, IL-17, IFN-γ, and IL-2/4/6/10), worsening psoriasis through the JAK-STAT and NF-κB pathways, which inhibit apoptosis and promote angiogenesis. NF-κB activation leads to IR, higher insulin and C-peptide levels, and increased androgen levels, intensifying sebaceous gland activity and promoting acne. Obesity is associated with Th1/Th22 cell activation and elevated IL-3/4 levels, resulting in adipokine changes (abnormal adiponectin and elevated resistin) and endothelial inflammation (McP-1, VCAM-1, and ICAM-1), indicating autoimmune dysfunction. Dysregulated lipid production promotes Cutibacterium acnes colonization, exacerbating acne. Enhanced IGF-1 and increased EGF and TGF-β2 levels cause excessive cell differentiation and proliferation, contributing to psoriasis and SLE. Oxidative stress damages intracellular proteins and DNA, increasing the risk of autoimmune disorders, including vitiligo and SLE. CVD risk is elevated because of TLR4/JNK/MAPK pathway activation, increasing TNF-α, IL-1β, and IL-6 levels. Mitochondrial dysfunction leads to diabetes, with lipid ROS causing further cellular damage. This overview highlights the complex relationship between diet, immune response, MetS, and skin diseases, providing a foundation for future research and targeted therapeutic strategies

IR is a significant feature of MetS and is associated with the pathogenesis of psoriasis and CVD. Disruption of the PI3K/Akt signaling pathway by IR may exacerbate the onset of psoriasis (Table 2) [15]. Furthermore, mTOR pathway activation in IR and psoriatic lesions further promotes lesion development (Fig. 1) [16, 17].

Table 2.

Signaling pathway in MeTS and skin-related conditions

Metabolic syndrome	TLR4/JNK, MAPK, PI3K/Akt, mTOR
Psoriasis	PI3K/Akt, mTOR
Lichen planus	JAK-STAT, MAPK and NF-κB
Acne	mTOR, PI3K/AKT, NF-κB
Systemic lupus erythematosus	mTOR

mTOR, the mechanistic target of the rapamycin pathway; TLR4/JNK, toll-like receptor 4/c-Jun N-terminal kinase pathway; MAPK, mitogen-activated protein kinase; PI3K/Akt, phosphoinositide 3-kinase/Akt; JAK-STAT, Janus kinase-signal transducer and activator of transcription; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells

Adipokines, including leptin and resistin, play pro-inflammatory roles in psoriasis and MetS. Leptin expression is enhanced in patients with obesity and psoriasis and is positively correlated with disease severity [18, 19], whereas increased resistin levels are correlated with MetS risk [20]. Low levels of adiponectin are associated with the development of MetS, indicating its role in regulating IR and metabolism [21].

Oxidative stress is a critical link between psoriasis and MetS. It connects these two diseases through reactive oxygen species (ROS) imbalance and antioxidant insufficiency, influencing disease severity and metabolic dysregulation [22, 23]. Endoplasmic reticulum stress plays a significant role in MetS and psoriasis, affecting inflammatory responses and cellular metabolic pathways [24, 25]. Pro-inflammatory mediators induced by endoplasmic reticulum stress in various immune cells may mediate the comorbidity mechanisms of these diseases. Genetic factors contribute to the association between psoriasis and MetS, with identified shared susceptibility genes, including CDKAL1, IL23R, IL12B, IL23A, ST6GAL1, PTPN22, and JAZF1 [26].

Dysbiosis of gut microbiota plays a crucial role in psoriasis and MetS. Patients with psoriasis exhibit fewer intestinal microbes, particularly Akkermansia muciniphila, than healthy individuals do. This microbe is closely associated with the prevention of metabolic dysregulation, positively correlated with levels of fatty acid oxidation and brown fat, and inversely correlated with IR, cardiovascular risk, and obesity, potentially linking psoriasis and MetS [27, 28].

Comprehensive treatment strategies for psoriasis and MetS necessitate careful drug selection and consideration of the patients’ overall health. Traditional psoriasis therapies such as cyclosporine and acitretin may adversely affect metabolism. Cyclosporine exacerbates hypertension, while acitretin may induce lipid abnormalities. Consequently, monitoring metabolic status before prescribing these medications to patients with psoriasis is imperative. A previous study reported that methotrexate not only effectively improves psoriasis severity but may also treat MetS [29]. However, further prospective research is required to confirm this potential benefit.

Previous research reported that antidiabetic medications, including thiazolidinediones and biguanides, alleviate inflammation in psoriasis by modulating signaling pathways [30]. Glucagon-like peptide-1 (GLP-1) receptor agonists, including semaglutide and liraglutide, demonstrate potential in ameliorating cutaneous lesions in patients with comorbid type 2 diabetes and psoriasis [31]. This is probably because of their ability to regulate glucose and lipid metabolism and inhibit IL-23, -17, -22, and TNF-α in the skin tissue. A meta-analysis revealed the efficacy of statin therapy in improving psoriasis symptoms, although contradictory reports on the exacerbation of psoriasis exist. These medications offer new treatment options for patients with psoriasis, particularly for those with concurrent MetS [32].

Biological agents targeting TNF-α and IL-17 have demonstrated significant therapeutic potential for psoriasis and MetS [33, 34]. Adalimumab effectively improves psoriatic lesions and enhances metabolic parameters, including lipid and glucose levels, thereby reducing cardiovascular risk. Hence, TNF inhibitors may be preferred for patients with psoriasis and MetS. However, studies have indicated a better treatment response among patients with a normal body mass index (BMI) than among those with a high BMI, with some risk of weight/BMI increase associated with TNF-α inhibitors. IL-17 inhibitors from phase III clinical observations demonstrate no risk of weight gain; however, patients with normal BMI often exhibit better efficacy than those with obesity of overweight.

Apremilast, a phosphodiesterase 4 inhibitor, demonstrates good safety and potential for weight reduction [35] and is particularly effective for patients with obesity and MetS [36].

In addition to pharmacotherapy, lifestyle modifications are essential in treating psoriasis and MetS. Regular physical activity, healthy diet, weight management, and smoking cessation positively impact symptom management in both conditions. Bariatric surgery for morbidly obese patients with psoriasis correlates with reduced severity of psoriasis after weight loss. Regular screening for MetS-related symptoms, such as blood pressure, lipids, and glucose levels, is critical for controlling psoriasis severity and reducing CVD risk.

Lichen planus (LP)

LP is significantly associated with MetS, particularly in relation to IR and dyslipidemia among patients with LP. Large-scale studies by Jieya Ying et al. have demonstrated a significantly higher prevalence of MetS in patients with LP than in the general population, with a particular emphasis on dyslipidemia [37]. The association between LP and dyslipidemia manifests as elevated levels of serum TG, cholesterol, and LDL cholesterol (LDL-C) and decreased levels of high-density lipoprotein cholesterol (HDL-C) [38]. Dyslipidemia is inversely correlated with disease duration [39]. LP severity is associated with the risk of MetS, with lower occurrence rates observed in mild LP cases [40]. Furthermore, different clinical presentations of LP, especially those involving mucosal lesions [40] and oral LP [41], demonstrate higher rates of MetS.

The association between LP and MetS involves multiple physiological and pathological mechanisms, primarily centered on chronic inflammation, immune responses, lipid metabolism disorders, and oxidative stress. LP, a T cell-mediated autoimmune disease, involves the over-activation of Th1 cells and related cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and interferon [IFN]-γ) (Table 1) [41], causing chronic inflammation that leads to skin and mucosal damage. These pro-inflammatory cytokines are implicated in LP and contribute significantly to MetS development by activating signaling pathways, including JAK-STAT, MAPK, and nuclear factor kappa B (NF-κB) (Table 2), thereby promoting systemic chronic inflammation and increasing the risk of IR, obesity, and hypertension (Fig. 1) [37]. The long-term release of cytokines under chronic inflammatory conditions disrupts normal lipid metabolism, resulting in elevated levels of serum TG and LDL-C and decreased levels of serum HDL-C [42], which are hallmark features of MetS. Dyslipidemia is more prevalent among patients with LP, particularly those with mucosal involvement [43], due to intensified chronic inflammation and immune responses. Increased oxidative stress levels in patients with LP may lead to lipid peroxidation, which can damage cellular proteins and DNA [44]. This oxidative damage exacerbates LP skin symptoms and may increase MetS risk, creating a vicious cycle of inflammation and exacerbating the severity of LP and MetS [45].

As inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, statins are essential in lipid-lowering therapy. Despite studies associating statins with LP-like eruptions in hyperlipidemia treatment [46], statins possess antioxidant, anti-inflammatory, and leukocyte activation inhibitory properties, potentially beneficial in LP treatment [47]. Accordingly, statins may positively affect LP treatment in MetS management. Glitazones (peroxisome proliferator-activated receptor agonists, PPAR agonists) activate genes involved in fatty acid metabolism, demonstrating potential efficacy in LP treatment by lowering lipid levels [48].

The systemic administration of acitretin and glucocorticoids may affect lipid homeostasis. Acitretin may increase TG and cholesterol levels while decreasing HDL levels [49], and glucocorticoids may induce lipolysis and very LDL synthesis, resulting in increased free fatty acid release [50]. These effects are critical in LP management and can potentially negatively impact MetS management. Kumar et al. [51] reported that screening patients with LP for blood lipids and glucose is crucial for the early detection and management of LP, and this strategy simultaneously supports MetS management.

Sebaceous and apocrine gland disorders

Acne

The association between acne and MetS is a complex clinical and epidemiological topic. Acne severity is positively correlated with the incidence of MetS [52], although the findings of different studies have been inconsistent.

Acne is associated with several MetS factors, including IR, hypertension, and dyslipidemia [53]. A previous study reported that patients with acne have higher rates of IR and MetS than controls, especially post-adolescent male patients with acne, which may be an indicator of prediabetes [52]. Additionally, Franik et al. [54] reported that elevated serum-free testosterone levels are associated with a higher risk of severe acne, which positively correlates with increased blood glucose levels. Furthermore, individuals with a larger waist circumference are more susceptible to developing acne [55], further supporting the association between acne and MetS.

In females, acne is associated with polycystic ovary syndrome (PCOS), which is closely associated with MetS [56]. In addition, studies have indicated that acne in females correlates with IR and changes in lipid profiles but not with hyperandrogenism [57].

Several key pathways are involved in the mechanisms underlying the co-occurrence of acne and MetS. IR plays a pivotal role in acne development by elevating insulin levels, thereby increasing the insulin-like growth factor-1 (IGF-1) activity. Elevated IGF-1 levels contribute to higher serum dihydrotestosterone and dehydroepiandrosterone sulfate levels, intensifying sebaceous gland activity, promoting hyperkeratosis, and enhancing testosterone synthesis, further facilitating acne development [58]. Additionally, hyperinsulinemia increases epidermal growth factor and transforming growth factor-β levels, leading to elevated levels of non-esterified fatty acids, which subsequently trigger inflammation and exacerbate acne [59].

Moreover, endocrine disruptions in patients with PCOS, characterized by IR, decreased sex hormone-binding globulin levels and elevated free testosterone levels, exacerbate the pathological processes of acne and are closely associated with MetS [60]. These biological changes are associated with IR, a critical component of MetS, which plays a central role in metabolic dysregulation.

Acne is closely associated with enhanced activity of the mechanistic target of the rapamycin complex 1 (mTORC1) pathway. Western dietary habits (high sugar, carbohydrate, and dairy consumption) and adolescence are major risk factors [53]. These factors activate the PI3K/AKT signaling pathway, stimulate mTORC1 activity, affect lipid production, promote Cutibacterium acnes colonization, and enhance biofilm formation (Table 2). Furthermore, elevated IGF-1 stimulates testosterone synthesis and modulates testosterone receptor signal transduction, exacerbating acne development [61, 62].

Recent research has indicated that oxidative stress, inflammatory mediators, prothrombotic components, leptin, homocysteine, and resistin concentrations, and decreased adiponectin levels in serum are potential factors linking MetS and common acne [63]. Additionally, pilosebaceous unit dysfunction may play a significant role in MetS development, as changes in sebum secretion can contribute to its pathogenesis [64].

Investigating the integrated treatment strategies for acne and MetS highlights the pivotal role of metformin. Its role in inhibiting mTORC1 activity is significant in acne management and has been established as an effective adjunct therapy for acne treatment [65]. Furthermore, metformin has demonstrated beneficial effects on various aspects of MetS, including dysglycemia, obesity, and hepatic dysfunction [66]. Its anti-inflammatory effects involve reducing prostaglandin E2, nitric oxide, and pro-inflammatory cytokines (IL-1, IL-6, and TNF-α), mediated through the inhibition of NF-κB activation in macrophages [67]. These cytokines play intermediate roles in various skin inflammatory reactions.

Minocycline has anti-inflammatory properties that improve blood glucose control in patients with insulin resistance and protect end-organ damage in patients with diabetes [68]. This highlights the critical role of glycemic control in acne therapy. Oral isotretinoin remains an effective acne treatment despite its side effects on serum lipid levels, necessitating the crucial monitoring of lipid profiles in patients with acne. Studies further suggest that vitamins and supplements, including vitamins A, E, D, zinc, and selenium, can ameliorate acne by reducing oxidative stress intensity and MetS processes. However, caution is advised against excessive intake of vitamin B12, which may exacerbate inflammatory lesions [69].

Furthermore, a previous study reported that low glycemic index and low glycemic load diets effectively reduced sebaceous gland size, decreased IGF-1 and Sterol Regulatory Element Binding Protein 1 expression, and lowered inflammatory responses, thereby improving clinical symptoms of acne [70]. This demonstrates the need to address the dietary and metabolic factors in acne treatment strategies.

Consequently, comprehensive treatment approaches for acne and MetS should include pharmacological interventions, dietary adjustments, and lifestyle modifications. This multidimensional approach improves MetS symptoms and effectively treats acne, highlighting the synergistic therapeutic interactions among these conditions.

Rosacea

A systematic review and meta-analysis by Li et al. revealed significant associations between rosacea and several cardiovascular risk factors, including hypertension, dyslipidemia, and MetS [71]. Akin Belli et al. found significantly elevated rates of IR, fasting blood glucose, LDL, TG, and C-reactive protein (CRP) levels in patients with rosacea [72]. Furthermore, lifestyle factors, including alcohol consumption and smoking, are implicated in rosacea onset and are risk factors for MetS [73]. These findings indicate systemic metabolic abnormalities in patients with rosacea.

The association between rosacea and MetS reveals complex interactions involving systemic inflammation, metabolic abnormalities, neurovascular dysregulation, and unhealthy lifestyles. Increased expression of inflammatory cytokines and antimicrobial peptides is notable in patients with rosacea. The upregulation of these molecules is closely associated with pathophysiological processes in MeTS, including chronic inflammatory conditions, disturbances in sympathetic nervous system regulation, and effects on testosterone levels [63, 74].

Moreover, MetS promotes systemic inflammation and arterial wall dysfunction, potentially explaining the association between rosacea and hypertension [75]. Patients with dyslipidemia and rosacea exhibit reduced serum paraoxonase-1 activity, an HDL-associated antioxidant enzyme [76]. These studies provide crucial perspectives for understanding the complex interactions between rosacea and MetS, revealing potential shared pathophysiological mechanisms and therapeutic targets.

Statins effectively lower lipid levels and inhibit matrix metalloproteinase (MMP) secretion implicated in rosacea and CVD pathogenesis [77]. β-Blockers, proposed as off-label treatments for rosacea, are suitable for erythematotelangiectatic rosacea and potentially influence cardiovascular risk [78]. Besides, tetracycline exhibits anti-inflammatory properties in rosacea treatment, reducing rosacea incidence and potentially protecting the cardiovascular system through its inhibitory effects on MMP activity [79]. Potential adverse effects should be considered when selecting treatments; for instance, isotretinoin therapy for rosacea may elevate serum cholesterol and TG levels and cause rhabdomyolysis when used concomitantly with statins [80].

In clinical practice, screening for metabolic comorbidities is recommended in patients with rosacea. Oral aspirin or low-dose doxycycline is recommended in patients with multiple risk factors [81]. Furthermore, patients are encouraged to lose weight, exercise regularly, and quit smoking and alcohol consumption to reduce the risk of rosacea and MetS.

Hidradenitis suppurativa (HS)

HS is a chronic inflammatory skin disease that involves the follicular units of the pilosebaceous apparatus. Previous studies have demonstrated a positive correlation between HS and MetS [82, 83]. The prevalence of MetS among patients with HS ranges from 10.4 to 50.6% [82–85], varying with patient type (general versus severe) and age groups (adults versus children) [86]. Recent reviews estimate that patients with HS have an OR of 2.66 (95% CI 1.90–3.72) for developing MetS [87].

Significant associations exist between HS and all other components of MetS, except for hypertension. Patients with HS exhibited significantly elevated levels of serum TG, glucose, and insulin and lower HDL-C levels.

Gould et al. [84] found no correlation between MetS severity and HS. However, Kevin Phan et al. [86] suggested a higher risk of MetS in patients with severe HS than those with mild HS, although this finding was statistically non-significant. Accordingly, further research is required to confirm this association.

Chronic inflammation, endocrine dysfunction, and adipose tissue alterations are the primary factors underlying the association between HS and MetS [86]. Chronic inflammation is implicated in HS pathogenesis, with increased levels of inflammatory cytokines, including TNF-α, IL-1β, and IL-6 [88], which are closely associated with IR and MetS development.

Obesity is another significant factor in this relationship. Increased body surface area in obese individuals may predispose them to HS through increased sweating and mechanical friction-induced follicular occlusion [85]. Moreover, obese individuals exhibit a higher number of adipocytes, which are critical for energy storage and secretion of various adipokines, including increased expression of pro-inflammatory adipokines such as resistin, leptin, and visfatin, and decreased expression of anti-inflammatory adipokine adiponectin [89, 90]), contributing to IR and inflammation in HS and MetS [83].

Furthermore, patients with HS exhibit IR due to imbalances in adipokines associated with obesity, which promote a pro-inflammatory state. IR increases the production of inflammatory factors and exacerbates the pathologic processes of HS through mTORC1 pathway overexpression [86]. Genetic factors and lifestyle-related factors, including diet and physical activity, influence the association between HS and MetS [86].

The significant association between HS and MetS underscores the importance of its simultaneous management in clinical practice. Contraceptives and anti-androgen therapy, including spironolactone, are effective in reducing pain and inflammation associated with HS [91–93]. Additionally, metformin and other antidiabetic medications exhibit potential in controlling HS symptoms, highlighting the pivotal roles of insulin and glucose in HS pathogenesis [94]. PPAR ligands, including rosiglitazone, have been successfully used to treat diabetes and psoriasis by normalizing epidermal keratinization [95].

Currently, there are two approved immunotherapies for HS: The TNF-α antagonist adalimumab and the IL-17A neutralizing antibody, secukinumab [96, 97]. Compared with psoriasis, these biologics are beneficial to only a subset of patients with HS. Other biologics, including IL-23, IL-1, and JAK inhibitors, are under investigation to target additional inflammatory pathways associated with HS [97, 98].

Lifestyle adjustments, particularly healthy diets and weight reduction, are crucial for HS management. A previous study reported that Western diets rich in a high glycemic index and fats may exacerbate HS, whereas diets rich in fruits and vegetables may alleviate HS symptoms [99]. Low serum levels of zinc and vitamin D are associated with increased HS lesions, and supplementation with these substances and vitamin B12, magnesium, or the exclusion of dairy products or brewer's yeast can partially or completely resolve HS lesions [100]. Low-glycemic index diets may help alleviate HS symptoms, with studies indicating that the GLP-1 agonist liraglutide effectively reduces HS symptoms and improves weight and blood glucose levels associated with MetS [101]. Furthermore, while weight loss surgery can improve disease conditions by reducing weight, it may lead to malabsorptive malnutrition, which can worsen or induce new HS [102]. These findings align with the current theories involving Th17 cells and mTOR kinase in HS inflammation and pathogenesis. Future studies are required to further define and determine the role of diet in HS [100]. Increasing exercise and smoking cessation are the recommended methods for reducing HS severity. Through this multidimensional approach, HS symptoms can be improved while managing MetS, thereby enhancing overall quality of life and health status.

Hair loss disease

Androgenetic alopecia (AGA)

AGA is significantly associated with MetS. A previous meta-analysis revealed that patients with AGA have a 2.3–3.46 times higher risk of developing MetS than healthy controls [103]. This association is particularly significant in women, which may be attributed to a high prevalence of PCOS [103]. However, a study in the Chinese population found no association between AGA and MetS, although a close association between AGA and systolic blood pressure was identified [104], suggesting an ongoing debate in this area.

Analyzing the association between AGA and MetS components yielded inconsistent outcomes across studies. Early-onset AGA demonstrates higher weight, waist circumference, HDL, TG, and fasting blood glucose levels in males than in normal controls [105]. Among female patients with AGA, increased severity of hair loss corresponds to higher rates of obesity and hypertension [106]. Waist circumference (OR 5.6, 95% CI 2.2–13.9, p = 0.0002) and hypertension (OR 3.5, 95% CI 1.3–8.9, p = 0.008) are significant factors in MetS development in patients with AGA [106]. These symptoms may be associated with IR, decreased sex hormone-binding globulin, a chronic inflammatory response, and neuroendocrine abnormalities.

Genetics and androgens are considered primary factors in AGA pathogenesis. Elevated serum testosterone levels and sensitive follicular androgen receptors promote MetS development in AGA. This exacerbates hypertension, hypercholesterolemia, and atherosclerosis [107], potentially aggravating IR, endothelial dysfunction, and inflammation.

Moreover, chronic inflammation is implicated in AGA onset and progression. Inflammatory cytokines, including IL-1 and TNF-α, mediate long-term chronic inflammation, with IL-1 associated with IR and TNF-α contributing to follicular degeneration and hair loss (Table 1, Fig. 1) [108]. These findings highlight the higher risks of hypertension and dyslipidemia among patients with AGA than among the general population, emphasizing the need for MetS screening in patients with AGA.

MetS treatment is complex and challenging for patients with early-onset AGA. Common MetS medications, including rosuvastatin [109], metformin [110], and Lisinopril [111], may not achieve optimal outcomes in these patients, suggesting a need for more personalized treatment strategies. Additionally, vitamin D [112] and levothyroxine [113] supplementation demonstrated some positive effects in patients with AGA.

Female pattern hair loss

The relationship between female pattern hair loss (FPHL) and MetS is a complex yet increasingly clear area of study. Several studies have attempted to investigate the direct association between FPHL and MetS. A study of 45 Egyptian women demonstrated a significantly increased prevalence of MetS in the FPHL group than in controls, particularly as the severity of hair loss increased [106]. Among the various characteristics of MetS, waist circumference, hypertension, and FPHL are significantly correlated, with increased waist circumference being positively associated with FPHL severity [106]. Moreover, patients with FPHL often exhibit abnormal lipid levels, including elevated TG, low HDL-C, and increased fasting blood glucose or diabetes risk [106, 114].

The association between FPHL and MetS primarily manifests as IR and hyperandrogenism. IR leads to increased insulin and androgen levels, directly affecting follicle function and causing hair loss [106]. Elevated androgen levels in MetS affect the hair follicle lifecycle, exacerbating hair loss while increasing sebaceous gland activity, leading to acne and oily skin [115]. Furthermore, MetS is associated with chronic inflammation, which further compromises follicle health and exacerbates hair loss issues [116]. These mechanisms collectively explain the complex relationship between FPHL and MetS.

FPHL treatment complicated by MetS should involve a comprehensive approach, including pharmacotherapy and lifestyle modifications. Topical minoxidil promotes hair growth and ameliorates FPHL symptoms. Anti-androgen medications, including spironolactone, effectively treat FPHL by reducing circulating androgen levels or blocking androgen receptors [117]. Oral contraceptives help in managing symptoms associated with hyperandrogenism by regulating hormone levels [116]. Healthy diets and regular exercise improve insulin sensitivity and aid in MetS management, thereby improving hair loss conditions [118]. Personalized treatment plans and multidisciplinary teamwork are crucial for ensuring treatment efficacy [115].

Alopecia areata (AA)

AA is an autoimmune-mediated follicular disease closely associated with metabolic factors. Lee et al. reported that the prevalence of MetS among patients with AA was 37.3%, which was significantly higher than that in the general population [119]. Studies have indicated a higher incidence of metabolic disturbances in patients with AA, and a meta-analysis conducted in 2023 revealed a higher prevalence of MetS (OR 5.03, 95% CI 4.18–6.06; prevalence 1.4%) and hyperinsulinemia (OR 3.52, 95% CI 1.43–8.71; prevalence 60.8%) [120]. IR is implicated in AA onset and progression, as evidenced by significantly elevated serum insulin levels, C-peptide levels, and homeostasis model assessment of IR (HOMA-IR) in patients with AA [121]. Elevated levels of inflammatory cytokines, including IFN-γ, TNF-α, IL-2, and IL-15, in patients with AA further highlight the potential association between AA and MetS (Table 1) [122]. Adiponectin reduces inflammatory cytokine production. Stochmal et al. found decreased serum levels of adiponectin and resistin in patients with AA, highlighting the importance of metabolic factors in AA pathogenesis [123].

However, a case–control study in Northwestern India found no significant correlation between MetS and IR among patients with AA in the local population [122]. Nevertheless, the study proposed several hypotheses, including interactions between neuroendocrine and immune systems leading to changes in the hypothalamic–pituitary–adrenal HPA axis, oxidative stress imbalance, and increased inflammatory cytokines. These factors may represent the shared pathogenic mechanisms between AA and MetS.

These data suggest an increased risk of metabolic disturbances, particularly IR and increased inflammatory cytokine levels, among patients with AA. Consequently, screening for MetS and IR is crucial for the effective management of patients with AA.

Allergic skin diseases

Atopic dermatitis (AD)

Recent studies have demonstrated an increasing association between AD and MetS. A previous study comprising 86,969 children with AD reported that they exhibited 1.61 times higher odds of developing MetS (95% CI 1.28–2.01), 1.87 times higher odds of developing hyperlipidemia (95% CI 1.69–2.06), and 1.81 times higher odds of developing obesity (95% CI 1.70–1.91) than controls [124]. Similarly, another study demonstrated significantly increased risks of hyperlipidemia, hypertension, and type 2 diabetes in patients with AD [125]. Some studies have suggested a negative correlation between AD and diabetes, associating AD with lower overall diabetes risk (OR 0.89, 95% CI 0.80–0.99) and type 2 diabetes (OR 0.83, 95% CI 0.76–0.90) [126].

Overall, the relationship between AD and MetS remains incompletely elucidated. A recent review that included 14 studies evaluated the AD-MetS relationship and reported that this association may not be causal [127]. However, AD is positively correlated with various components of MetS, including central obesity and hypertriglyceridemia, particularly in females [128]. Previous studies have reported that AD severity correlates with the prevalence of metabolism-related diseases, particularly among patients with severe AD [129, 130].

AD primarily manifests through T helper 2 (TH2)/TH22 cytokine immune profiles, particularly those mediated by IL-4 and IL-13 responses (Table 1, Fig. 1) [131]. While the exact mechanisms of the association between AD and MetS remain unclear, researchers, including Hu, have suggested that impaired insulin signaling, IR, and elevated chronic inflammatory states are major risk factors linking the two [132]. Both AD and MetS affect T-cell cytokine expression, and the association between adult AD and metabolic abnormalities may be based on an “inflammatory skin progression model” [133]. This model hypothesizes that pro-inflammatory cytokines from Th1, Th17, and Th22 cells activate downstream pathways through cytokine receptor binding, thereby driving the connection between AD and MetS [134]. Additionally, the excessive release of pro-inflammatory cytokines, including TNF-α and IL-1, from AD may lead to chronic low-grade systemic inflammation, which is central to the pathophysiology of IR, visceral obesity, hypertension, and dyslipidemia. A previous study identifying the role of resistin in AD reported that endothelial cells exhibited increased expression levels of inflammatory markers, including MCP-1, VCAM-1, and ICAM-1 [135], while adiponectin levels were reduced in AD, possibly due to its anti-inflammatory effects [136]. These factors contribute to MetS. Weight reduction improves AD treatment outcomes [137].

Seborrheic dermatitis (SD)

SD is associated with elevated blood lipid levels, IR, hypertension, and increased waist circumference. A previous study reported that the severity of facial SD is associated with elevated levels of LDL and TG, decreased HDL levels, and IR [138]. Erdoğan et al. [139] reinforced this association, revealing a significantly higher prevalence of IR among patients with SD than healthy controls. These findings suggest a potentially shared inflammatory pathophysiology between SD and IR.

SD emerges as a common symptom associated with MetS in studies of skin manifestations in patients with obesity. Research on metabolic and hormonal changes in patients with SD over 40 years of age has highlighted disturbances in lipid metabolism, particularly increases in cholesterol, LDL, and atherosclerosis indices [140]. Besides, there is a notable familial history of metabolic disorders among patients with SD, suggesting a genetic predisposition or familial trend [141]. These studies reveal the complex interaction between SD and MetS, indicating that metabolic and inflammatory factors are implicated in SD pathogenesis.

While the current research provides valuable insights, further studies are necessary to investigate the exact relationship between these conditions and identify more effective treatment and management strategies.

Urticaria

Chronic urticaria (CU) exhibits a complex interaction with MetS. A community-based cross-sectional study involving 11,261 patients demonstrated a significant association between CU and MetS, obesity, diabetes, hyperlipidemia, hypertension, chronic kidney disease, and gout [142].

Ye et al. [143] reported that South Korean patients with CU exhibited a higher prevalence of MetS. These patients exhibited higher urticaria activity scores and elevated levels of eosinophil cationic protein, TNF-α, and complement proteins in their serum. CU exhibits pathological mechanisms similar to those of MetS, including pro-inflammatory states, increased oxidative stress, altered adiponectin levels, and activation of the coagulation system [142].

Furthermore, a significant association was observed between urticaria and obesity. Choudhary and Shrestha [144] reported that 69% of patients with CU were overweight or obese, suggesting a role for obesity in urticaria pathogenesis. The significance of obesity in relation to urticaria stems from its high occurrence as a common component of MetS, often being the first component, followed by others.

The relationship between CU and MetS is multifaceted. While the current research has not definitively revealed direct links and mechanisms between these two conditions, the studies mentioned above provide clues toward understanding their potential relationship. Further research is required to comprehensively understand the interaction between these conditions.

Antihistamines are widely used to treat urticaria, which may lead to weight gain and MetS. Obesity is a potential side effect of H1 antihistamines. Furthermore, they may induce higher insulin concentrations [145]. Anvari et al. reported that cetirizine did not affect insulin sensitivity or diabetes development but protected against hyperglycemia induced by a high-fat diet in Nod mice (a model for human type 1 diabetes) [146]. Few reports have indicated that some patients treated with omalizumab for type 2 diabetes may experience impaired glycemic control, with significant increases in fasting blood glucose and HOMA-IR values, even in patients without diabetes [147]. It is advisable to monitor blood glucose levels and IR during omalizumab therapy, particularly in patients with diabetes and those at a high risk of diabetes.

Connective tissue diseases and vasculitis

Systemic lupus erythematosus (SLE)

SLE is an autoimmune disease associated with an increased risk of MetS, ranging from 18 to 30% [148]. A meta-analysis revealed increased risks of MetS, hyperglycemia, dyslipidemia, hypertension, and central obesity among patients with SLE than among controls, with TG and blood pressure demonstrating the most significant increases [149]. Scholars suggest that MetS may accelerate chronic systemic inflammation and atherosclerosis in SLE [150]. Previous meta-analyses on SLE-MetS revealed SLE as a risk factor for MetS [151].

Previous studies have reported that multiple pathways, including mitochondrial dysfunction and immune-metabolic dysregulation, induce oxidative stress, leading to inflammation and MetS onset in patients with SLE [152, 153]. Rhoads et al. [154] observed an increased expression of glucose transporter in CD4+ T cells, highlighting IR and abnormal fasting insulin levels as the primary factors contributing to metabolic abnormalities in patients with SLE.

Obesity can induce a pro-inflammatory state, increasing the expression of pro-inflammatory molecules, including IL-17, IL-23, and TNF-α, which may play pivotal roles in SLE pathogenesis (Table 1) [155]. Abnormal serum levels of adiponectin [150], elevated resistin levels, decreased anti-inflammatory cytokines, growth hormone-releasing peptides, and antioxidant concentrations in patients with SLE demonstrate a complex interaction between the immune system and MetS [156]. These findings significantly contribute to understanding the association between SLE and MetS and provide crucial insights for future therapeutic strategies and interventions.

Hydroxychloroquine is widely used to treat SLE and discoid lupus erythematosus because of its favorable metabolic effects on glucose and lipid profiles. This may be a favorable choice for patients with diabetes. A previous study reported that patients with SLE receiving hydroxychloroquine experienced reductions in triglyceride and lipoprotein levels, increased HDL, decreased IR, and lower fasting blood glucose levels (Fig. 1) [157].

A large randomized clinical trial revealed that vitamin D supplementation significantly reduced autoimmune risk [158]. Vitamin D deficiency is associated with autoimmune conditions, including SLE [159]. Obesity in the general population correlates with vitamin D deficiency, suggesting a potential association between obesity, vitamin D deficiency, and SLE pathogenesis [159].

Metformin is a first-line medication for lowering blood glucose levels in patients with type 2 diabetes. It may be beneficial for patients with SLE by reducing mitochondrial oxidative stress in immune cells [160]. Small open-label and randomized double-blind clinical trials have demonstrated the beneficial effects of metformin in reducing disease activity in patients with mild SLE when used adjunctively with conventional therapy, primarily prednisone. Metformin reduces disease activity, delays disease onset, and decreases the amount of prednisone required to maintain remission [161, 162].

The mTOR pathway activation drives inflammatory phenotypes in lupus T cells (Table 2) [163]. Treatment with mTOR inhibitors, including rapamycin and sirolimus, has demonstrated therapeutic efficacy in patients with SLE [164].

Behçet’s syndrome (BD)

BD is a chronic inflammatory autoimmune multisystem disorder that affects multiple organs, including the skin mucosa, gastrointestinal tract, eyes, blood vessels, musculoskeletal, and central nervous systems. The association between BD and MetS is supported by multiple studies, revealing complex interactions between inflammation and metabolic dysregulation.

Patients with BD and MetS are at increased risk for mucocutaneous, musculoskeletal, neuro-psychiatric, and ocular symptoms, with higher incidence rates of ocular manifestations [165]. Patients with BD are more susceptible to MetS components, including diabetes, hypertension, and dyslipidemia, compared to the general population, indicating a significant association [166]. However, this conclusion remains controversial, as a large-scale retrospective cohort study found a reduced risk of developing BD in patients with MetS [167]. In Egyptian patients, no significant relationship was observed between BD and MetS, suggesting an influence of regional and ethnic variations on this association [168].

Pro-inflammatory cytokines, including IL-1, IL-6, IL-8, and TNF-α, are implicated in BD (Table 1) [169]. Elevated inflammatory markers may lead to IR, endothelial dysfunction, and MetS onset [170]. Additionally, IR has been implicated in the association between BD and MetS, with studies indicating higher IR and lower insulin sensitivity in patients with BD than in healthy controls [171]. Moreover, adipokines, including leptin, resistin, adiponectin, visfatin, and apelin, are significantly elevated in patients with BD, potentially contributing to MetS development [172]. Dysregulation of regulatory T-cell function is associated with BD development and hypertension [173].

The relationship between BD and MetS is likely driven by inflammation, endothelial dysfunction, IR, and abnormal adipokine levels. BD and MetS negatively impact the quality of life and psychological health of patients [174], suggesting that psychological factors may affect their development (Fig. 1).

IL-1 receptor antagonists, including anakinra, have demonstrated efficacy in managing inflammation associated with BD and MetS [175]. Additionally, vitamin D supplementation as an immune modulator can improve immune function in patients with BD and aid in managing metabolic disturbances [176].

Vasculitis

MetS is significantly associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across multiple dimensions, including increased incidence rates, disease relapse, and risk of severe complications. Approximately 43% of patients in the ANCA-associated vasculitis group meet the criteria for MetS, compared to 25% in the healthy control group (p = 0.012) [177]. This finding demonstrates a significant correlation between MetS and AAV.

Additionally, MetS is correlated with a more pro-inflammatory state in patients with AAV and may increase the risk of disease relapse. Petermann Smits et al. reported that patients with AAV with concomitant MetS experience higher rates of relapse than those without MetS [178]. Lower total cholesterol levels may predict disease relapse in these patients [179]. Furthermore, MetS in patients with AAV correlates with an increased risk of CVD [180] and kidney-related complications. Park et al. reported that MetS severity independently predicts the risk of developing end-stage renal disease in patients with MetS and AAV [181]. The triacylglycerol and glucose (TyG) index highlights the association between MetS and AAV, where a higher TyG index indicates an increased risk of MetS and poorer cumulative survival rates in acute coronary syndrome. Moreover, patients with higher Birmingham vasculitis activity scores exhibit elevated risk of acute coronary syndrome [182].

These studies suggest that MetS may exacerbate AAV severity and progression, potentially increasing the risk of severe complications, including CVD and kidney failure. Future studies must clarify the exact mechanisms behind these associations.

Autoimmune bullous diseases

Autoimmune bullous diseases are a group of diverse autoimmune disorders characterized by blister formation on the skin and mucous membranes. Previous studies have demonstrated an association between pemphigus group diseases and MetS [183]. A Brazilian study linked MetS to the autoimmune skin disease pemphigus; however, long-term steroid therapy is considered a potential confounding factor [183].

A previous study demonstrated a higher prevalence of MetS among patients with pemphigoid group diseases. A 12-year case–control study in China reported a 35.2% prevalence of MetS among patients with pemphigoid compared to 14.8% in the control group [184]. MetS and its components, including hyperglycemia and overweight, are independently associated with pemphigoid group diseases. Moreover, a previous study demonstrated an established association between psoriasis and MetS, suggesting a potential coexistence with autoimmune bullous diseases, primarily bullous pemphigoid (BP). The study proposed that IL-17 might be a common factor linking BP with psoriasis and MetS coexistence (Table 1) [185].

However, most related studies lack specific information on the relationship and underlying mechanisms between pemphigus or pemphigoid disease and MetS. This indicates that, while a connection exists, research in this field is insufficient to fully clarify the detailed mechanisms and deeper relationships between the two.

Patients with autoimmune bullous diseases, especially those with MetS, require careful monitoring and management. Physicians should consider the potential adverse effects of long-term glucocorticoid use, which may further exacerbate MetS risk. Consequently, treatment approaches that minimize side effects, including the administration of biologics or metformin [186], may help improve the overall health of these patients. The relationship between autoimmune bullous diseases and MetS highlights the complexity that needs to be considered in treating and managing autoimmune skin diseases, emphasizing the importance of comprehensive metabolic health assessment and monitoring for these patients.

Pigmentary skin diseases

Vitiligo

The association between MetS and vitiligo has been confirmed in multiple studies. Vitiligo is an autoimmune skin disease characterized by the destruction of melanocytes and the loss of pigmentation. Research indicates a higher prevalence of MetS among patients with vitiligo than among the general population. A study that included 228 participants found a significant association between vitiligo and MetS, where the severity of vitiligo, the extent of body involvement, and disease duration were identified as independent risk factors for MetS [187]. Further investigations revealed that patients with vitiligo exhibit decreased HDL levels, impaired glucose tolerance, and elevated triglyceride levels, which are typical symptoms of MetS [188].

A previous meta-analysis revealed a strong association of vitiligo with diabetes (OR 3.30, 95% CI 2.10–5.17) and obesity (OR 2.08, 95% CI 1.40–3.11) [189]. Additionally, the prevalence of hypertension among patients with vitiligo was 19.0%, with a higher fasting glucose index and diastolic pressure than controls [190]. Furthermore, IR, elevated insulin, and C-peptide levels were significantly increased in patients with vitiligo [191]. Another study found lower HDL levels and higher LDL-C levels in patients with vitiligo, indicating a predisposition to metabolic dysregulation [192, 193]. However, recent meta-analyses suggest that patients with vitiligo do not necessarily have a higher risk of MetS compared to controls (OR 1.66, 95% CI 0.83–3.33, p = 0.01) [194].

Regarding the mechanistic similarities between vitiligo and MetS, studies propose autoimmune dysfunction, increased pro-inflammatory cytokines, enhanced oxidative stress, and genetic susceptibility as common factors. The melanocyte destruction in patients with vitiligo stems from autoimmune dysfunction triggered by genetic and environmental factors [74]. Melanocyte loss affects skin pigmentation, potentially impacting metabolic processes. The absence of melanocytes could increase the risk of MetS in patients with vitiligo due to their antioxidant and anti-inflammatory properties, which mitigate oxidative stress and inflammatory responses induced by adipose tissue [74]. Furthermore, elevated levels of pro-inflammatory cytokines, including TNF-α, IL-1, and IL-6 in serum and adipose tissues, are implicated in vitiligo pathogenesis and are associated with IR, atherosclerosis, and other metabolic complications (Table 1) [195].

Further studies revealed that patients with vitiligo often exhibit elevated inflammatory markers, including neutrophil-to-lymphocyte ratio, CRP, and homocysteine. The increase in these inflammatory markers is associated with an increased risk of MetS due to compromised antioxidant and anti-inflammatory functions owing to melanocyte deficiency (Table 1) [196, 197]. Homocysteine inhibits tyrosinase in melanocyte synthesis, another potential factor in vitiligo pathogenesis, and elevated homocysteine levels are known risk factors for CVD, further emphasizing the potential pathophysiological connection between vitiligo and MetS [198]. A genome-wide association study identified susceptibility loci in patients with vitiligo that are strongly associated with diabetes, including IFIH1, BACH2, BTNL2, IL2RA, SH2B3, and ZMIZ1 (Fig. 1) [199].

Certain treatments for vitiligo have demonstrated cardiovascular benefits. Bae et al. reported that patients with vitiligo who received narrow-band ultraviolet radiation b(UVB) phototherapy exhibited a significantly lower risk of subsequent cardiovascular events than untreated individuals. Notably, this treatment did not affect diabetes, hypertension, or dyslipidemia in these patients [200].

Simvastatin, an effective statin drug, inhibits the production of pro-inflammatory cytokines, which are implicated in vitiligo pathogenesis [201]. Case reports by Noor et al. described repigmentation in patients with vitiligo treated with high-dose simvastatin, attributing its effects to immune modulation of CD8+ T cells in melanocytes inhibited by IFN-γ [202]. An in vitro study by Chang et al. reported that simvastatin protects cells from apoptosis induced by H₂O₂ and ROS accumulation, highlighting its potential role in vitiligo treatment [203]. Simvastatin blocks the PI3k/Akt signaling pathway involved in T cell generation. Given these immunomodulatory properties, simvastatin may benefit patients with vitiligo while also helping prevent metabolic complications such as MetS [204].

Acanthosis nigricans (AN)

Ayaz et al. [205] demonstrated a significant correlation between MetS and AN, indicating positive associations with elevated TG, decreased HDL-C levels, and increased waist circumference. Daye et al. [206] reported a higher prevalence of MetS in obese children with AN. Philip et al. [207] reported that 78.3% of patients with AN exhibited MetS, with AN severity correlating with MetS incidence.

The relationship between AN and MetS can be realized through shared mechanisms of IR. During insulin-resistant states, excessive insulin production promotes the over-proliferation of epidermal keratinocytes and fibroblasts, leading to characteristic skin lesions in AN, including hyperpigmentation and velvety thickening [208, 209].

Obesity is implicated as a common factor in AN and MetS associations. In patients with obesity, hyperinsulinemia increases insulin receptor binding and decreases insulin-like growth factor-binding proteins, thereby enhancing the IGF-1 biological activity, which contributes to hyperkeratosis and acanthosis development [210]. Other previous studies reported that changes in adipocyte factors, including leptin, resistin, and adiponectin, may be implicated in AN pathogenesis. Higher levels of leptin and lower levels of adiponectin were observed in patients with AN [20].

Oral medications are effective for the widespread treatment of AN. Oral retinoids, including isotretinoin, have been successfully used to treat extensive AN associated with obesity. However, maintaining therapeutic efficacy may require continuous administration of topical medications or other oral agents, including metformin [211]. Careful monitoring is essential due to the potential adverse effects of retinoids, such as long-term teratogenicity and hypertriglyceridemia.

Metformin is effective in improving AN and IR [210]. Combination therapy with metformin and thiazolidinediones has been found beneficial in enhancing insulin sensitivity and treating AN [210, 212]. For women with hyperandrogenism, IR, and AN, the combined use of metformin and oral contraceptives is an effective treatment strategy [212, 213].

Insulin sensitizers, including alpha-lipoic acid, have also demonstrated potential in AN treatment. A randomized controlled trial comparing metformin with Canthex™, which contains alpha-lipoic acid, reported both to be similarly effective [214]. Beyond pharmacotherapy, low-calorie diets and appropriate physical exercise positively impact IR and alleviate AN skin symptoms.

Fibroproliferative disorders

Keloids

Limit epidemiological studies exist on the association between keloids and MetS, yet multiple studies provide evidence that patients with keloids often present with metabolic disorders, including obesity, hypertension, dyslipidemia, and diabetes. Studies have indicated a higher incidence of keloids within these patient groups, potentially linked to the diseases themselves and their interrelationships [215].

A case–control study analyzed the association of keloids with hypertension and obesity, suggesting a connection between these comorbidities and keloid development [216]. Hypertension exacerbates the severity of keloids, with patients with multiple or large keloids more likely to clinically manifest hypertension [217]. Additionally, patients with severe hypertension are more susceptible to developing multiple and/or large keloids [218]. Patients with diabetes experience a significantly increased risk of keloid formation following trauma due to elevated blood glucose levels and associated complications [219]. Chronic wounds in patients with diabetes, often occurring at keloid-prone sites, significantly heighten the risk of keloid formation [220]. Olopoenia et al. [215] found a higher prevalence of dyslipidemia among patients with keloids. Furthermore, an association between dyslipidemia and osteoporosis in patients with keloid highlights metabolic dysregulation in keloid formation.

Although mechanisms underlying keloid formation in association with MetS are unknown, they are hypothesized to involve systemic effects on wound healing and fibroblast activity. Prolonged hyperglycemia induces oxidative stress and inflammation, exacerbating fibroblast proliferation and collagen synthesis in keloid tissue [221]. Lipid molecules and their metabolites influence mechanical signaling pathways in keloid development, highlighting potential metabolic dysregulation in fibrotic diseases [222]. Obesity induces chronic inflammation and altered adiponectin secretion, which are implicated in keloid development and severity [223]. Adipose tissue dysfunction in obesity further promotes an inflammatory milieu conducive to keloid formation [224]. Hypertension may aggravate keloid formation through endothelial dysfunction, increased blood flow, altered vascular tension, and dysregulated coagulation pathways [225]. These vascular changes activate fibroblasts and lead to excessive collagen deposition in keloid scar tissue [225].

Effective management of keloids in patients with MetS involves targeted therapeutic approaches addressing metabolic dysregulation and scar formation. Medications targeting MetS components, including angiotensin-converting enzyme inhibitors (captopril) and calcium channel blockers (verapamil), are effective in keloid treatment [226, 227]. Furthermore, dipeptidyl peptidase-4 inhibitors administered for diabetes indirectly impact keloid and hypertrophic scar formation by enhancing insulin secretion and improving wound healing outcomes in patients with diabetes [228]. Adjusting diet to manage lipid levels, weight reduction strategies, and controlling blood pressure complement pharmacotherapy, synergistically reducing keloid severity and recurrence rate [217].

Cutaneous tumors

Nagel et al. investigated the association between MetS and skin cancer, particularly melanoma (MM). They observed a positive correlation between hypertension and MM risk. Notably, males with MM tend to have a higher BMI, whereas females with squamous cell carcinoma or non-melanoma skin cancer (NMSC) often exhibit elevated blood glucose and triglyceride levels [229]. An Iranian case–control study demonstrated a significantly higher prevalence of MetS among patients with NMSC than among healthy controls (p = 0.038). MetS and its components were associated with increased NMSC risk [230]. In males, metabolism-associated fatty liver disease is associated with increased risks of various cancers, including liver cancer, esophageal cancer, pancreatic cancer, colorectal cancer, anal cancer, bladder cancer, and malignant melanoma [231].

Combining these findings, MetS components and related disease states are intricately associated with skin cancer. However, the precise relationship and underlying mechanisms between melanoma and MetS remain unclear. Future research should clarify the association between these two conditions.

This review systematically integrates recent epidemiological, mechanistic, and therapeutic evidence regarding MetS and skin diseases, covering a wide range of conditions from inflammatory (e.g., psoriasis, acne) to autoimmune (e.g., lupus, pemphigus) and neoplastic diseases. Integrating perspectives from dermatology and metabolic medicine highlights common pathophysiological mechanisms, particularly IR, systemic inflammation, and adipokine dysregulation, and underscores potential therapeutic approaches (e.g., metformin for acne, TNF-α inhibitors for psoriasis with MetS) that can simultaneously improve dermatological manifestations and metabolic abnormalities. Such an integrative viewpoint not only helps dermatologists more effectively identify hidden metabolic risks but also encourages interdisciplinary collaborations, ultimately enhancing patient outcomes and overall quality of life.

Despite its broad coverage, this review has certain limitations. First, the included studies exhibit considerable heterogeneity in their designs, study populations, and definitions of MetS, which may affect the comparability and consistency of findings. Second, the potential for publication bias cannot be excluded, as studies with smaller sample sizes or negative results are less likely to be published. Third, the most available research in this field is observational, limiting the ability to establish causality. Prospective, large-scale, and mechanistic studies are necessary to determine whether improving metabolic parameters directly alters the clinical course of dermatological diseases. Finally, although shared molecular pathways are highlighted, specific mechanistic details remain insufficiently explored in less-studied skin conditions, warranting further investigation.

Conclusion

Herein, we reviewed the association between MetS and skin diseases, clarifying their shared physiological and metabolic mechanisms and potential interactions (Fig. 2). From IR and chronic inflammatory states to dyslipidemia, MetS promotes a spectrum of cardiovascular and metabolic diseases and closely correlates with the pathophysiology of various skin diseases. Research on the association of MetS with psoriasis, AD, acne, and other skin diseases enhances our understanding of their pathophysiological basis and provides new perspectives for clinical treatment.

Fig. 2.

Relationship between MetS and skin diseases. MetS is associated with various skin diseases through multiple pathways. These pathways include oxidative stress leading to DNA and protein damage, IR contributing to hyperinsulinemia, lipid metabolism abnormalities affecting steroid synthesis, chronic inflammation mediated by cytokines, including TNF-α and IL-1, and genetic factors influencing susceptibility to conditions such as psoriasis and vitiligo. The interconnected mechanisms highlight the complexity of managing skin diseases in patients with MetS

From a clinical standpoint, recognizing the interaction between MetS and dermatologic disorders can significantly improve how dermatologists screen and manage patients. Early identification of metabolic abnormalities (for instance, obesity, dyslipidemia, and IR) in individuals with chronic inflammatory or autoimmune skin conditions enables a more holistic treatment strategy. Therefore, dermatologists can collaborate more effectively with endocrinologists and primary care physicians, tailoring interventions such as lifestyle modification, targeted biologic agents, or insulin-sensitizing therapies to achieve better outcomes. By integrating metabolic considerations into routine dermatologic practice, patient care can be optimized, leading to reductions in cardiovascular risk, improved quality of life, and potentially greater dermatologic treatment success.

Owing to the pivotal impact of MetS on both skin disease progression and systemic health, integrating MetS screening and management into standard dermatological practice should be a priority. Future research should examine the specific interaction mechanisms between these two diseases, develop personalized treatment approaches, and investigate early intervention and preventive measures to mitigate the adverse impact of MetS on skin health. These studies will offer essential support for clinical practice, thereby improving the overall health and quality of life of patients.

Author contributions

JLX: writing—original draft, investigation. LD: writing—original draft, validation. GYL: writing—review and editing, project administration.

Funding

The author(s) declare no financial support was received for the research, authorship, and/or publication of this article.

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.