Atopic dermatitis (AD) is a chronic inflammatory skin disease that is prevalent worldwide with complex etiology. Skin barrier defects and abnormal immune activation are crucial in the occurrence and development of AD. In the classic model of the skin barrier, lipids are essential for the formation and maintenance of this barrier as a "mortar" component. However, abnormally activated immune responses promote the lipid barrier deficiency through the secretion of various types of immune mediators directly or indirectly. In this review, we first introduce the skin lipid barrier (SLB) under both normal and abnormal conditions, highlighting the contributions of lipids derived from keratinocytes and sebaceous glands (SGs). Subsequently, the relationships between the immune mediators of Th1, Th2, Th17, Th22, and other types (adipokines, prostaglandins, leukotrienes) and SLB are elaborated in turn. Finally, the therapies for restoring SLB to treat AD are summarized, with a focus on the restoration effect of dupilumab on SLB. We hope that this review will offer a comprehensive perspective for understanding the pathogenesis of lipid metabolism disorders and SLB deficiency caused by immune mediators in AD. It also aims to provide guidance for further research on targeting inflammatory mediators to restore SLB.

Natural killer (NK) cells produce various cytokines, including interleukin (IL)‑1β, IL‑6, IL‑10, IL‑12, interferon γ, tumor necrosis factor α and transforming growth factor β, which are critical in modulating immune responses. NK cell‑conditioned medium (NK‑CdM), rich in cytokines, has potential applications in therapy and healing. The present study aimed to investigate the protective effect of NK‑CdM against ultraviolet B (UVB)‑mediated photoaging using in vitro and ex vivo models. In human keratinocyte cell line (HaCaT cells), NK‑CdM mitigated UVB‑induced cytotoxicity and suppressed the production of reactive oxygen species. NK‑CdM enhanced the mRNA expression levels of superoxide dismutase 1 (SOD1) and catalase (CAT) and inhibited the reduction in SOD1 and CAT expression levels caused by UVB irradiation. Furthermore, NK‑CdM inhibited the UVB‑mediated nuclear translocation of nuclear factor erythroid 2‑related factor 2. NK‑CdM also prevented UVB‑induced downregulation of filaggrin and involucrin and attenuated the UVB‑induced reduction in hyaluronan synthase (HAS)1, HAS2, HAS3, aquaporin‑3 and hyaluronan levels. Notably, NK‑CdM upregulated the expression of elongation of very long chain fatty acids (ELOVL) enzymes, including ELOVL1, ELOVL5 and ELOVL6, as well as ceramide synthases (CerS), specifically CerS2 and CerS3. Furthermore, NK‑CdM inhibited the UVB‑induced reduction in the levels of these proteins. Overall, these findings suggested that NK‑CdM has the potential to prevent UVB‑mediated photoaging and promote skin health.

Inhibition of IL-4/IL-13-driven inflammation by dupilumab has shown significant clinical benefits in treatment of atopic dermatitis (AD).

Our aim was to assess longitudinal protein and metabolite composition in AD skin during dupilumab treatment.

Skin tape strips (STSs) were collected from lesional/nonlesional skin of 20 patients with AD during a 16-week dupilumab treatment course and from 20 healthy volunteers (HVs) followed for 16 weeks. STS extracts were examined by liquid chromatography-mass spectrometry proteomic analysis and targeted metabolomics.

Approximately 2500 individual proteins were identified in the STS extracts. Of those proteins, 490 were present in at least 80% of the AD and HV skin samples and differentially expressed in the AD skin; the levels of 249 proteins were significantly reduced (cluster 1), and the levels of 136 were significantly increased (cluster 2) in the AD skin versus in the HV skin (both P < .0001). Functionally, cluster 1 included proteins involved in epidermal barrier formation, lysosomal enzymes required for lamellae assembly, and oxidative response. Cluster 2 was enriched for markers of epidermal hyperplasia, glycolytic enzymes, and actin filament proteins. A significant increase in cluster 1 and a significant inhibition of cluster 2 proteins expression were achieved in AD skin by 16 weeks of dupilumab treatment (P < .0001 for both vs baseline), approaching the levels in HV skin. These improvements were also revealed in differential metabolite changes in the STS extracts, including amino acids, nucleotide breakdown products, and antioxidants.

Longitudinal integrated assessment of the skin proteome and metabolome in patients with AD who were treated with dupilumab established significant inhibition of epidermal hyperplasia and improvement in epidermal differentiation. The identified changes were linked to improvements in clinical AD skin assessments, including improvements in transepidermal water loss and disease severity.

For highly efficient and precise drug release, transdermal drug delivery systems (TDDS) have recently evolved through the combination of intelligent material-based structures with various active components. These strategies are an effort to overcome the significant difficulties in delivering large molecule drugs and nanomaterials due to the physical barrier of the skin, especially the stratum corneum, in traditional TDDS. Interestingly, multiscale suction-driven architectures (SDAs) inspired by bioinspired suction adhesion mechanisms have provided innovative solutions to these challenges. These architectures employ negative pressure to enhance nanoscale skin-controllable skin adhesion, temporarily bypass the skin barrier, and facilitate deep penetration of therapeutic agents, thereby, achieving the goals of increasing drug delivery efficiency and maximizing user convenience as a minimal invasive, needle-free platform. This review provides a comprehensive overview of suction-driven transdermal patches and emphasizes their integration with multifunctional materials to achieve stable adhesion and controlled drug release. Next, we present cost-effective and user-friendly suction-driven drug delivery patch devices through optimization of cupping structures without the incorporation of additional devices. Furthermore, we present cost-effective and user-friendly transdermal drug delivery patch devices that optimize multiscale cupping architectures without the need for additional devices. Potential of bioinspired SDAs in localized and systemic drug delivery through challenging and complex skin, as well as future perspectives, are discussed, along with innovative directions for more efficient and patient-centric transdermal drug delivery solutions.

Changes in the stratum corneum (SC) lipid profiles are associated with various skin diseases. Factors, including age, ethnicity, season and anatomical location, can influence the variations in SC lipid profiles. According to reports, the facial sebum of Chinese women peaks at age 20-30, accompanied by various signs of facial ageing. No studies have investigated how facial SC lipid profiles change with age in young Chinese women.

This study aimed to observe the differences in the facial SC lipid profiles of Chinese female volunteers aged 19-33 and determined the relationship between key lipids and physiological parameters.

Differential lipids were detected and screened in healthy Chinese women aged 19-33 through ultra-performance liquid chromatography-mass spectrometry. The relationship between these lipids and the skin's physiological parameters was determined.

The facial SC lipid profiles of young Chinese women exhibited significant differences with age. The results indicated that 40 lipids increased with age, while 51 types decreased. The average chain length of diglycerides (DG), triglycerides (TG) and short-chain ceramides decreased with age, while cholesterol esters (CE) and ceramides {Cer, Cer/EODS (d19:0/18:1/O/16:0) and Cer/EOS (d28:1/12:0/O/14:0)} increased with age. Cer/EODS (d19:0/18:1/O/16:0), Cer/EOS (d28:1/12:0/O/14:0) and HexCer/NDS (d14:0/33:1) were positively correlated with trans-epidermal water loss, skin elasticity and skin brightness, while Cer/AP (t18:0/20:0) was negatively correlated with skin elasticity. This study comprehensively explains the differences in lipid profile composition and skin ageing in young populations.

Young Chinese women's facial skin SC lipid profiles significantly change with age. Age-related changes result in variations in DG and CE levels and changes in the chain lengths of TG and Cer. Age-related changes in Cer content affect skin barrier function, elasticity and brightness.

The stratum corneum (SC) lipids provide the main barrier of the skin against the environment. Ceramides make up about half of the lipids by weight and are thus of particular interest. Emulsifiers are used in a multitude of topical formulations, e.g., to stabilize emulsions against coalescence. Investigations showed that some emulsifiers have the potential to impair skin barrier function. Sorbitan esters (SEs) are frequently used emulsifiers in pharmaceutical and cosmetic dermal formulations. Further, cholesterol and lecithin were used as natural alternatives. However, information on their impact on ceramides is very scarce. Thus, we first analyzed the SEs by LC-MS with regard to their composition. Then we developed an LC-MS method to identify and quantify the ceramides in porcine skin and subsequently investigated the impact of emulsifiers on the ceramide profile. Besides the LC-MS measurements, the effect of emulsifiers on the skin barrier function was investigated by trans-epidermal water loss (TEWL) measurements and confocal Raman spectroscopy (CRS). Throughout the experiments, water was used as a negative control and sodium lauryl sulfate (SLS) as a positive control. It was found that SEs are mixtures of mono-, di-, and triesters, partially with a complex fatty acid distribution. LC-MS measurements of the total ceramide content of the SC samples revealed the SE 60 and cholesterol-treated samples to be those showing the least ceramide depletion, implying a high skin tolerability in general. The TEWL measurements showed that SEs 40, 60, 80, and 120 showed no significant changes in skin barrier function. The lipid content, measured by CRS, was mostly decreased except for SE 120. Conformation, chain order, and SC thickness, also measured by CRS, showed no significant differences. These detailed investigations lead to the view that SEs are skin-friendly substances and can be used for topical applications, e.g., those commonly used to treat skin diseases.

Atopic dermatitis involves the head and neck area across all age groups. This manifestation is frequently referred to as "the head and neck dermatitis." Aside from a considerable deterioration of the quality of life, it poses a significant diagnostic and therapeutic challenge. The head and neck dermatitis may be mimicked by other inflammatory conditions such as seborrheic dermatitis or contact dermatitis. Furthermore, it can be associated with a wide range of infectious, ocular, psychiatric and hair disorders, which should raise clinical alertness and encourage a multidisciplinary management of the affected individuals. Skin lesions in the head and neck area are often difficult to treat, particularly because of a considerable exposure of this region to exacerbating factors and limitations regarding the use of some pharmaceuticals. Although several hypotheses explaining the recalcitrant course of head and neck dermatitis have been proposed, none of them provide successful solutions applicable in the daily clinical practice. This comprehensive review comprises the current insights on the pathogenesis, clinical presentation, and comorbidities of the head and neck dermatitis. Recommendations regarding possible treatments of this condition such as antifungals, as well as special considerations for the choice of biologics or JAK inhibitors in the candidates for systemic treatment are outlined.

Although sensitive skin (SS) is a syndrome characterized by cutaneous hypersensitivity to environmental factors, its pathophysiology remains elusive.

We aimed to explore the characteristics of ceramides (CERs) and intercellular lipid (ICL) structures of individuals with and without facial SS and their relationship with skin hypersensitivity.

Healthy Japanese females were divided into SS or non-SS groups based on self-perception and lactic acid stinging test (LAST). Stratum corneum (SC) lipids were analyzed using a liquid chromatograph-mass spectrometer, and the orthorhombic-hexagonal lateral packing structure of ICLs was assessed using electron diffraction.

According to the mean LAST score, individuals with SS (n = 48) had mild-to-moderate skin hypersensitivity. SS exhibited not significantly but slightly impaired skin barrier function (p = 0.072) and lower levels of CER[NH], [NP], [EOS], [EOH] (all p < 0.05), and [EOP] (p = 0.073) in the SC compared with non-SS (n = 18). Notably, the CER[NP]/[NS] ratio, a marker of skin barrier function, was positively correlated with the orthorhombic-hexagonal lateral packing ratio of ICLs (p = 0.002), whereas it was negatively correlated with the LAST score (p = 0.015) and the interleukin (IL)-1 receptor antagonist/IL-1α ratio (p = 0.003) in the SC, an indicator of chronic inflammation. Moreover, corneocyte size was reduced in SS (p < 0.001), suggesting inferior SC maturation, and was positively correlated with the CER[NP]/[NS] (p < 0.001) and the orthorhombic-hexagonal ratios (p = 0.011).

Individuals with SS showed an abnormal CER profile, particularly the altered CER[NP]/[NS] ratio, which was in turn associated with disordered ICL structure and skin hypersensitivity. Abnormal epidermal turnover may be an underlying mechanism of the abnormalities.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder influenced by both genetic and environmental factors, collectively termed the exposome. Among these determinants, diet emerges as a pivotal component, with diverse nutrients, contaminants, and additives shaping immune responses, microbiota composition, and systemic inflammatory status. This literature review aimed to elucidate the interplay between dietary factors and skin dysbiosis in AD, providing insights into how these interactions may impact disease susceptibility and progression. A comprehensive search of PubMed and Scopus was conducted using relevant keywords and medical subject headings (MeSH). Studies published in English within the past 25 years were included, encompassing in vitro, in vivo, and ex vivo research, as well as reviews. Priority was given to frequently cited articles, reflecting significant contributions to current understanding. Findings suggest that dietary habits influence AD by modulating both gut and skin microbiota, immune pathways, and inflammatory processes. These insights underscore the importance of considering diet within a broader exposome framework, paving the way for targeted interventions to improve AD management. Further research is needed to clarify the mechanisms and optimize nutritional strategies, potentially informing preventive and therapeutic approaches for AD.

Skin lipids are crucial components of the skin barrier. Individuals with atopic dermatitis (AD or eczema) have a different skin lipid profile from those without. However, whether altered skin lipids precede and predict the subsequent risk of AD remained unclear, especially for different AD phenotypes.

We sought to examine the relationship between skin lipids and subsequent AD and AD phenotypes in infants.

Skin lipids from the forearms of 133 infants with family history of allergic disease were sampled using tape strips at age 6 weeks. Lipids were quantified using liquid chromatography-tandem mass spectrometry. AD by age 1 year was diagnosed using modified UK Working Party Criteria. Allergic sensitization was assessed using skin prick tests. Associations and predictive discrimination were estimated using univariable logistic regression. Potential causation was explored using multivariable logistic regression.

Reduced levels of 6 protein-bound ω-hydroxyl sphingosine (POS) ceramides with C30 and C32 fatty acids at 6 weeks were associated with increased risk of AD by age 1 year. In univariate models, a number of POS ceramides predicted subsequent AD, such as PO30:0-C20S (area under the curve, 0.65; 95% CI, 0.55-0.75). After confounders were adjusted, only PO30:0-C20S was associated with AD (adjusted odds ratio, 0.62; 95% CI, 0.39-0.96 per 1-SD increase), and a trend for AD without sensitization (adjusted odds ratio, 0.57; 95% CI, 0.31-1.05) but not AD with sensitization (adjusted odds ratio, 0.76; 95% CI, 0.39-1.47).

Reduced levels of POS ceramides are associated with the development of nonatopic AD, suggesting that these lipids may play a role in the pathogenesis of AD and may be useful predictive biomarkers. Interventions that increase POS ceramides may reduce the incidence of AD.

Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (ie, dupilumab). The molecular mechanisms regulating S aureus levels between AD subjects remain poorly understood.

We investigated host genes that may be predictive of S aureus abundance and correspond with AD severity.

We studied data derived from the National Institutes of Health/National Institute of Allergy and Infectious Diseases-funded (NCT03389893 [ADRN-09]) randomized, double-blind, placebo-controlled multicenter study of dupilumab in adults (n = 71 subjects) with moderate-to-severe AD. Bulk RNA sequencing of skin biopsy samples (n = 57 lesional, 55 nonlesional) was compared to epidermal S aureus abundance, lipidomic, and AD clinical measures.

S aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both nonlesional (r = 0.29, P = .030) and lesional (r = 0.41, P = .0015) skin. Lesional CERS1 expression also positively correlated with AD severity (ie, SCORAD r = 0.44, P = .0006) and skin barrier dysfunction (transepidermal water loss area under the curve r = 0.31, P = .025) at baseline. CERS1 expression (forms C18:0 sphingolipids) was negatively associated with elongation of very long-chain fatty acids (ELOVL6; C16:0→C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S aureus abundance and ELOVL6 expression by day 21.

CERS1 is a unique molecular biomarker of S aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter-chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6.

Ceramide has transitioned from an incidental discovery to a vital element in skincare, becoming a thoroughly studied compound in the quest to treat skin conditions. Creating a moisture barrier, preserving hydration, regulating pH, controlling inflammation, and enhancing skin functions and appearance are among its established benefits. It is often used medically to repair skin barrier defects, as observed in inflammatory skin conditions like atopic dermatitis (AD) and dry skin types. Furthermore, ceramide and its metabolites are commonly used as predictors before disease manifestation and for prognostication processes, thus can be used as biomarker for clinical diagnosis as well. In the last couple of decades, momentum was also seen in the pre-clinical studies involving anti-cancer and nanotechnology field, whereby ceramide was also used as a drug, a carrier, or even adjunct formulation to increase efficacy of treatment such as chemotherapy. Approaches to increase ceramide levels include directly replenishing lost ceramides with natural extracts, synthetic pseudo-ceramides, or ceramide-like analogues, as well as using supplements that stimulate the body's natural ceramide production. Although ceramide is a well-known treatment in skincare and for common skin conditions like AD and psoriasis, its development and related pharmacology for severe skin conditions, such as skin cancer, remain in pre-clinical stages. Hence, the purpose of this research is to explore the role of ceramide in skin health and its application in common skin diseases.

Acne vulgaris (AV) is a common inflammatory disorder involving the pilosebaceous unit. Many studies have reported that people with AV have higher levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c) compared to healthy controls. Hence, they concluded that an unhealthy lipid profile is an independent risk factor for AV. Recent research in metabolomics and lipidomics has been propelled by rapid advancements in technologies including computational methods and mass spectrometry. Using metabolomics and lipidomics approach, a broad range of structurally diverse lipid species were detected and important lipid biomarkers were identified that are vital to the pathogenesis of AV. In this review, we will describe the recent progress in dyslipidemia of AV using metabolomics and lipidomics advances. We will begin with a literature overview of dyslipidemia of AV, followed by a short introduction of metabolomics and lipidomics. Finally, we will focus on applying metabolomics and lipidomics in dyslipidemia of AV.

Ceramides are key components of the skin's permeability barrier. In atopic dermatitis, pathological hydrolysis of ceramide precursors - glucosylceramides and sphingomyelin - into lysosphingolipids, specifically glucosylsphingosine (GS) and sphingosine-phosphorylcholine (SPC), and free fatty acids (FFAs) has been proposed to contribute to impaired skin barrier function. This study investigated whether replacing ceramides with lysosphingolipids and FFAs in skin lipid barrier models would exacerbate barrier dysfunction. When applied topically to human stratum corneum sheets, SPC and GS increased water loss, decreased electrical impedance, and slightly disordered lipid chains. In lipid models containing isolated human stratum corneum ceramides, reducing ceramides by ≥ 30% significantly increased permeability to four markers, likely due to loss of long-periodicity phase (LPP) lamellae and phase separation within the lipid matrix, as revealed by X-ray diffraction and infrared spectroscopy. However, when the missing ceramides were replaced by lysosphingolipids and FFAs, no further increase in permeability was observed. Conversely, these molecules partially mitigated the negative effects of ceramide deficiency, particularly with 5%-10% SPC, which reduced permeability even compared to control with "healthy" lipid composition. These findings suggest that while ceramide deficiency is a key factor in skin barrier dysfunction, the presence of lysosphingolipids and FFAs does not aggravate lipid structural or functional damage, but may provide partial compensation, raising further questions about the behavior of lyso(sphingo)lipids in rigid multilamellar lipid environments, such as the stratum corneum, that warrant further investigation.

The onset of atopic dermatitis (AD) is complex, and its specific pathological mechanisms have not yet been fully elucidated.

Using circulating multi-omics as the exposure factors and AD as the outcome, we conducted univariable MR analysis. The circulating multi-omics data included immunomics (731 immune cell types), proteomics (4907 plasma proteins), metabolomics (1400 metabolites and 486 additional metabolites), and 91 inflammatory factors. MR analysis was conducted using IVW, WM, Simple Mode, Weighted Mode, and MR-Egger methods, with IVW as the primary analysis tool. To address horizontal pleiotropy, we utilized MR-Egger intercept tests and MR-PRESSO for correction, alongside the Cochrane Q statistic for heterogeneity assessment. Sensitivity analysis was performed using a leave-one-out strategy. To control for false positives due to multiple testing, we set a standard of a 5% false discovery rate. Additionally, we conducted F-statistics on the included SNPs to eliminate the impact of weak instrumental variables.

IL-18R1 on AD (OR = 1.12, 95% CI: 1.08-1.17, P FDR < 0.01). Mannonate levels on AD (OR = 0.88, 95% CI: 0.83-0.94, P FDR = 0.03). Retinol (Vitamin A) to linoleoyl-arachidonoyl-glycerol (18:2 to 20:4) on AD (OR = 1.12, 95% CI: 1.06-1.18, PFDR = 0.03). HVEM on CM CD4+ cells on AD (OR = 0.81, 95% CI: 0.75-0.88, P FDR < 0.01). CR2 on AD (OR = 0.81, 95% CI: 0.72-0.90, P FDR = 0.04). MANSC1 on AD (OR = 0.87, 95% CI: 0.81-0.93, P FDR = 0.04). IL18R1 (4097 inflammatory markers) on AD (OR = 1.11, 95% CI: 1.06-1.17, P FDR = 0.01). HNRNPAB on AD (OR = 1.44, 95% CI: 1.23-1.70, P FDR < 0.01).

This study further explored the correlations between multi-omics data and AD. We identified seven previously unreported circulating substances with causal relationships to AD, filling a current theoretical gap.

The external ear canal, characterized by species-specific structural and physiological differences, maintains a hostile environment that prevents microbial overgrowth and foreign body entry, supported by factors such as temperature, pH, humidity, and cerumen with antimicrobial properties. This review combines several studies on the healthy ear canal's structure and physiology with a critical approach to the potential existence of an ear microbiome. We use a comparative multi-species approach to explore how allergic conditions alter the ear canal microenvironment and cerumen in different mammalian species, promoting pathogen colonization. We propose a pathogenetic model in which allergic conditions disrupt the antimicrobial environment of the EEC, creating circumstances favorable for facultative pathogenic micro-organisms like Staphylococcus and Malassezia species, leading to otitis externa (OE). A better understanding of the underpinning mechanisms may lead to innovative approaches to disease mitigation.

The skin is constantly exposed to environmental sensory stimuli, which may include harmful volatiles and small hydrophobic molecules. However, the skin's protective mechanism against the latter agents is unclear. Here, we demonstrate that odorant binding protein 2A (OBP2A) protects epidermal keratinocytes against cytotoxic small hydrophobic molecules. OBP2A is mainly expressed in human epidermal keratinocytes. Cellular resistance to cytotoxic aldehyde and lipids was reduced in keratinocytes when OBP2A was silenced. Furthermore, silencing of OBP2A in a three-dimensional epidermal equivalent model resulted in impairment of epidermal barrier function. Inhibition of OBP2A caused disruption of keratinocyte lipid metabolism and induced endoplasmic reticulum stress. OBP2A expression was markedly decreased in the epidermis of atopic dermatitis lesional skin. In addition, interleukin-13 suppressed the expression of OBP2A in keratinocytes. Overall, our findings suggest that OBP2A regulates epidermal barrier function and contributes to protection of the skin against harmful small hydrophobic molecules.

Atopic dermatitis is a chronic, recurrent, and multifactorial skin-mucosal manifestation resulting from the interaction between elements mainly associated with the skin barrier deficit, the homeostasis of the immune response, neurological aspects, and patterns of reactivity to environmental antigens, which are established in genetically predisposed individuals. In addition to the skin, atopic diathesis involves other organs such as the airways (upper and lower), eyes, digestive tract, and neuropsychiatric aspects, which inflict additional morbidity on the dermatological patient. The different phenotypes of the disease fundamentally depend on the participation of each of these factors, in different life circumstances, such as age groups, occupational exposure patterns, physical activity, pollution, genetic load, and climatic factors. A better understanding of the complexity of its pathogenesis allows not only the understanding of therapeutic targets but also how to identify preponderant elements that mediate disease activity in each circumstance, for selecting the best treatment strategies and mitigation of triggering factors. This narrative review presents an update on the pathogenesis of atopic dermatitis, especially aimed at understanding the clinical manifestations, the main disease phenotypes and the context of available therapeutic strategies.

Increasing evidence suggests a potential causal association between lipid levels and facial aging. The aim of this study was to investigate the relationship between levels of specific lipids and facial aging via Mendelian randomization methods. Additionally, this study aimed to identify mediators and explore relevant genes and drug targets.

In this study, genome-wide association data on plasma lipids from 7,174 Finnish individuals in the UK Biobank were used. Two-sample Mendelian randomization was applied to assess the causal effects of specific lipids on facial aging. Sensitivity and pleiotropy analyses were conducted to ensure the robustness and reliability of the results. Multivariate Mendelian randomization was conducted to account for the potential impact of confounding factors. Furthermore, summary-data-based Mendelian randomization was used to identify relevant genes, which were validated through multiomics data. Finally, drug‒gene interactions were explored via molecular docking techniques.

Two-sample Mendelian randomization analysis revealed a causal relationship between lipid levels and facial aging. According to the multivariate Mendelian randomization results, smoking was found to mediate this association, and these lipids remained significantly associated with facial aging, even after accounting for environmental confounders. Using summary-data-based Mendelian randomization, CYP21A2, CCND1, PSMA4, and MED1 were identified as potential gene targets, with MED1 further validated through pQTL and mQTL data. Additionally, the MED1 protein was found to bind spontaneously with astragalin, fenofibrate, and ginsenoside.

The results revealed a causal relationship between lipid levels and facial aging, revealing key gene targets that were still significantly associated with facial aging after controlling for environmental confounders. Additionally, the interactions between MED1 and certain drugs may indicate potential pathways for therapeutic interventions related to facial aging.

The skin epidermis provides a barrier that is imperative for preventing transepidermal water loss (TEWL) and protecting against environmental stimuli. The underlying molecular mechanisms for regulating barrier functions and sustaining its integrity remain unclear. RORα is a nuclear receptor highly expressed in the epidermis of normal skin. Clinical studies showed that the epidermal RORα expression is significantly reduced in the lesions of multiple inflammatory skin diseases. In this study, we investigate the central roles of RORα in stabilizing skin barrier function using mice with an epidermis-specific Rora gene deletion (RoraEKO). While lacking spontaneous skin lesions or dermatitis, RoraEKO mice exhibited an elevated TEWL rate and skin characteristics of barrier dysfunction. Immunostaining and Western blot analysis revealed low levels of cornified envelope proteins in the RoraEKO epidermis, suggesting disturbed late epidermal differentiation. In addition, an RNA-seq analysis showed the altered expression of genes related to "keratinization" and "lipid metabolism" in RORα deficient epidermis. A lipidomic analysis further uncovered an aberrant ceramide composition in the RoraEKO epidermis. Importantly, epidermal Rora ablation greatly exaggerated percutaneous allergic inflammatory responses to oxazolone in an allergic contact dermatitis (ACD) mouse model. Our results substantiate the essence of epidermal RORα in maintaining late keratinocyte differentiation and normal barrier function while suppressing cutaneous inflammation.

Psoriasis is an inflammatory skin disease associated with an impaired skin barrier. The skin barrier function is dependent on the extracellular lipid matrix which surrounds the corneocytes in the stratum corneum. Ceramides comprise essential components of this matrix. Alterations in the stratum corneum ceramide profile have been directly linked to barrier dysfunction and might be an underlying factor of the barrier impairment in psoriasis. In this study, we investigated the ceramide profile and barrier function in psoriasis. Lesional and non-lesional skin of 26 patients and 10 healthy controls were analysed using in-depth ceramide lipidomics by liquid chromatography-mass spectrometry. Barrier function was assessed by measuring transepidermal water loss. Lesional skin showed a significant decrease in the abundance of total ceramides with significant alterations in the ceramide subclass composition compared to control and non-lesional skin. Additionally, the percentage of monounsaturated ceramides was significantly increased, and the average ceramide chain length significantly decreased in lesional skin. Altogether, this resulted in a markedly different profile compared to controls for lesional skin, but not for non-lesional skin. Importantly, the reduced barrier function in lesional psoriasis correlated to alterations in the ceramide profile, highlighting their interdependence. By assessing the parameters 2 weeks apart, we are able to highlight the reproducibility of these findings, which further affirms this connection. To conclude, we show that changes in the ceramide profile and barrier impairment are observed in, and limited to, lesional psoriatic skin. Their direct correlation provides a further mechanistic basis for the concomitantly observed impairment of barrier dysfunction.

The longitudinal course of atopic dermatitis (AD) is heterogeneous and complex. While previously thought to be a childhood disorder, recent studies demonstrated that childhood-onset AD may take several different courses that may involve persistence into adulthood becoming a lifelong condition. Other patients only demonstrated adult-onset AD. Different factors may play a role in the timing of AD onset. Assessing the longitudinal course also involves understanding the changing temporal pattern of AD. Understanding the dynamic course of AD is important in identifying individualized treatment recommendations for patients.

Lipids are important skin components that provide, together with proteins, barrier function of the skin. Keratinocyte terminal differentiation launches unique metabolic changes to lipid metabolism that result in the predominance of ceramides within lipids of the stratum corneum (SC)-the very top portion of the skin. Differentiating keratinocytes form unique ceramides that can be found only in the skin, and generate specialized extracellular structures known as lamellae. Lamellae establish tight hydrophobic layers between dying keratinocytes to protect the body from water loss and also from penetration of allergens and bacteria. Genetic and immunological factors may lead to the failure of keratinocyte terminal differentiation and significantly alter the proportion between SC components. The consequence of such changes is loss or deterioration of skin barrier function that can lead to pathological changes in the skin. This review summarizes our current understanding of the role of lipids in skin barrier function. It also draws attention to the utility of testing SC for lipid and protein biomarkers to predict future onset of allergic skin diseases.

To highlight common mechanistic targets for the treatment of atopic dermatitis (AD) and IgE-mediated food allergy (IgE-FA) with potential to be effective for both diseases and prevent atopic progression.

Data sources were PubMed searches or National Clinical Trials (NCT)-registered clinical trials related to AD, IgE-FA, and other atopic conditions, especially focused on the pediatric population.

Human seminal studies and/or articles published in the past decade were emphasized with reference to preclinical models when relevant. NCT-registered clinical trials were filtered by inclusion of pediatric subjects younger than 18 years with special focus on children younger than 12 years as a critical period when AD and IgE-FA diseases may often be concurrent.

AD and IgE-FA share several pathophysiologic features, including epithelial barrier dysfunction, innate and adaptive immune abnormalities, and microbial dysbiosis, which may be critical for the clinical progression between these diseases. Revolutionary advances in targeted biologic therapies have shown the benefit of inhibiting type 2 immune responses, using dupilumab (anti-interleukin-4Rα) or omalizumab (anti-IgE), to potentially reduce symptom burden for both diseases in pediatric populations. Although the potential for biologics to promote disease remission (AD) or sustained unresponsiveness (IgE-FA) remains unclear, the refinement of biomarkers to predict infants at risk for atopic disorders provides promise for prevention through timely intervention.

AD and IgE-FA exhibit common features that may be leveraged to develop biologic therapeutic strategies to treat both conditions and even prevent atopic progression. Future studies should be designed with consistent age stratification in the pediatric population and standardized regimens of adjuvant oral immunotherapy or dose escalation (IgE-FA) to improve cross-study interpretation.

Atopic dermatitis (AD) is a common inflammatory skin disease, in particular among infants, and is characterized, among other things, by a modification in fatty acid and ceramide composition of the skin's stratum corneum. Palmitic acid and stearic acid, along with C16-ceramide and 2-hydroxy C16-ceramide, occur strikingly in AD. They coincide with a simultaneous decrease in very long-chain ceramides and ultra-long-chain ceramides, which form the outermost lipid barrier. Ceramides originate from cellular sphingolipid/ceramide metabolism, comprising a well-orchestrated network of enzymes involving various ELOVLs and CerSs in the de novo ceramide synthesis and neutral and acid CERase in degradation. Contrasting changes in long-chain ceramides and very long-chain ceramides in AD can be more clearly explained by the compartmentalization of ceramide synthesis. According to our hypothesis, the origin of increased C16-ceramide and 2-hydroxy C16-ceramide is located in the lysosome. Conversely, the decreased ultra-long-chain and very long-chain ceramides are the result of impaired ELOVL fatty acid elongation. The suggested model's key elements include the lysosomal aCERase, which has pH-dependent long-chain C16-ceramide synthase activity (revaCERase); the NADPH-activated step-in enzyme ELOVL6 for fatty acid elongation; and the coincidence of impaired ELOVL fatty acid elongation and an elevated lysosomal pH, which is considered to be the trigger for the altered ceramide biosynthesis in the lysosome. To maintain the ELOVL6 fatty acid elongation and the supply of NADPH and ATP to the cell, the polyunsaturated PPARG activator linoleic acid is considered to be one of the most suitable compounds. In the event that the increase in lysosomal pH is triggered by lysosomotropic compounds, compounds that disrupt the transmembrane proton gradient or force the breakdown of lysosomal proton pumps, non-HLA-classified AGEP may result.

Two-sample Mendelian randomization (TSMR) was employed to examine the association between lipidome and five inflammatory skin diseases.

To evaluate the association between various molecular subtypes of lipidome and the risk of five inflammatory skin diseases, we analyzed a comprehensive GWAS dataset comprising 179 lipidome. The Two-Sample Mendelian Randomization (TSMR) method was employed to investigate causal relationships. Heterogeneity and pleiotropy were assessed using Cochran's Q test, MR-Egger intercept test, and MR-PRESSO global test. Additionally, a sensitivity analysis was conducted to evaluate the influence of individual single nucleotide polymorphisms on Mendelian Randomization study.

Using 179 serum lipidome as exposures and five common inflammatory skin diseases as outcomes, we investigated their associations in this large-scale study. Our findings reveal significant impacts of glycerophospholipids, glycerolipids, and sphingomyelins on inflammatory skin diseases. Glycerophospholipids were protective against pemphigus but predominantly posed risks for other inflammatory skin diseases. Specifically, phosphatidylcholine (16:0_0:0) exhibited the most significant risk association with lichen planus (OR = 1.25, 95% CI 1.11-1.40, P < 0.001). Conversely, glycerolipids showed no effect on lichen planus but were protective against pemphigus while potentially posing risks for other conditions. Triacylglycerol (46:2) showed the most substantial risk association with vitiligo (OR = 1.99, 95% CI 1.35-2.93, P < 0.001). Furthermore, sphingomyelins had no effect on atopic dermatitis but posed potential risks for other inflammatory skin diseases. Sphingomyelin (d40:1) notably emerged as a significant risk factor for pemphigus (OR = 1.91, 95% CI 1.37-2.66, P < 0.001).

This study has elucidated the potential harmful effects of glycerophospholipids, glycerolipids, and sphingomyelins on inflammatory skin diseases, while also providing valuable insights for future research into the pathophysiology, prevention and treatment of these conditions.

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a TH2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, such as the gut, may be crucial for lowering the risk and preventing atopic diseases, particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in patients with atopic dermatitis, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1, and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and topical calcineurin inhibitors, along with pioneering trials proposed to change their current use (Prevention of Allergy via Cutaneous Intervention and Stopping Eczema and ALlergy). We provide an overview of the novel therapies that enhance the skin barrier, such as probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and interleukin and janus kinases inhibitors. Last, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy and the experimental use of single-dose of adeno-associated virus vector gene immunotherapy.

Persistent and unresolved inflammation is a common underlying factor observed in several and seemingly unrelated human diseases, including cardiovascular and neurodegenerative diseases. Particularly, in atopic conditions, acute inflammatory responses such as those triggered by insect venom, food or drug allergies possess also a life-threatening potential. However, respiratory allergies predominantly exhibit late immune responses associated with chronic inflammation, that can eventually progress into a severe phenotype displaying similar features as those observed in other chronic inflammatory diseases, as is the case of uncontrolled severe asthma. This review aims to explore the different facets and systems involved in chronic allergic inflammation, including processes such as tissue remodelling and immune cell dysregulation, as well as genetic, metabolic and microbiota alterations, which are common to other inflammatory conditions. Our goal here was to deepen on the understanding of an entangled disease as is chronic allergic inflammation and expose potential avenues for the development of better diagnostic and intervention strategies.

The epidermal inflammation associated with psoriasis drives skin barrier perturbations. The skin barrier is primarily located in stratum corneum (SC). Its function depends on the SC lipid matrix of which ceramides constitute important components. Changes in the ceramide profile directly correlate to barrier function. In this study, we characterized the dynamics of the barrier function and ceramide profile of psoriatic skin during anti-Interleukin-23 therapy with guselkumab. We conducted a double-blind, randomized controlled trial in which 26 mild-to-severe plaque psoriasis patients were randomization 3:1-100 mg guselkumab or placebo for 16 weeks and barrier dynamics monitored throughout. Barrier function was measured by trans-epidermal water loss measurements. Untargeted ceramide profiling was performed using liquid chromatography-mass spectrometry after SC was harvested using tape-stripping. The barrier function and ceramide profile of lesional skin normalized to that of controls during treatment with guselkumab, but not placebo. This resulted in significant differences compared to placebo at the end of the treatment. Changes in the lesional ceramide profile during treatment correlated with barrier function and target lesion severity. Nonlesional skin remained similar throughout treatment. Guselkumab therapy restored the skin barrier in psoriasis. Concomitant correlations between skin barrier function, the ceramide profile, and disease severity demonstrate their interdependency.

Ceramides are essential lipids for skin barrier function, and various classes and species exist in the human stratum corneum (SC). To date, the relationship between skin conditions and ceramide composition in healthy individuals has remained largely unclear. In the present study, we measured six skin condition parameters (capacitance, transepidermal water loss, scaliness, roughness, multilayer exfoliation, and corneocyte cell size) for the SC of the cheeks and upper arms of 26 healthy individuals and performed correlation analyses with their SC ceramide profiles, which we measured via liquid chromatography-tandem mass spectrometry. In the cheeks, high levels and/or ratios of two free ceramide classes containing an extra hydroxyl group in the long-chain moiety and a protein-bound ceramide class containing 6-hydroxysphingosine correlated with healthy skin conditions. In contrast, the ratios of two other free ceramide classes, both containing sphingosine, and a protein-bound ceramide class containing 4,14-sphingadiene correlated with unhealthy skin conditions, as did shortening of the carbon chain of the fatty acid portion of two ceramide classes containing non-hydroxy fatty acids. Thus, our findings help to elucidate the relationship between skin conditions and ceramide composition.

Allergic diseases display significant heterogeneity in their pathogenesis. Understanding the influencing factors, pathogenesis, and advancing new treatments for allergic diseases is becoming more and more vital as currently, prevalence continues to rise, and mechanisms of allergic diseases are not fully understood. The upregulation of the hypoxia response is linked to an elevated infiltration of activated inflammatory cells, accompanied by elevated metabolic requirements. An enhanced hypoxia response may potentially contribute to inflammation, remodeling, and the onset of allergic diseases. It has become increasingly clear that the process underlying immune and stromal cell activation during allergic sensitization requires well-tuned and dynamic changes in cellular metabolism. The purpose of this review is to examine current perspectives regarding metabolic dysfunction in allergic diseases. In the past decade, new technological platforms such as "omic" techniques have been applied, allowing for the identification of different biomarkers in multiple models ranging from altered lipid species content, increased nutrient transporters, and altered serum amino acids in various allergic diseases. Better understanding, recognition, and integration of these alterations would increase our knowledge of pathogenesis and potentially actuate a novel repertoire of targeted treatment approaches that regulate immune metabolic pathways.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a high prevalence worldwide. AD pathogenesis is complex and consists of immune system dysregulation and impaired skin barrier, influenced by genetic and environmental factors. The purpose of the review is to show the complex interplay between atopic dermatitis and the microbiota. Human microbiota plays an important role in AD pathogenesis and the course of the disease. Dysbiosis is an important factor contributing to the development of atopic diseases, including atopic dermatitis. The gut microbiota can influence the composition of the skin microbiota, strengthening the skin barrier and regulating the immune response via the involvement of bacterial metabolites, particularly short-chain fatty acids, in signaling pathways of the gut-skin axis. AD can be modulated by antibiotic intake, dietary adjustments, hygiene, and living conditions. One of the promising strategies for modulating the course of AD is probiotics. This review offers a summary of how the microbiota influences the development and treatment of AD, highlighting aspects that warrant additional investigation.

Skin tape-strips and biopsies are widely used methods for investigating the skin in atopic dermatitis (AD). Biopsies are more commonly used but can cause scarring and pain, whereas tape-strips are noninvasive but sample less tissue. The study evaluated the performance of skin tape-strips and biopsies for studying AD.

Whole-transcriptome RNA-sequencing was performed on paired tape-strips and biopsies collected from lesional and non-lesional skin from AD patients (n = 7) and non-AD controls (n = 5). RNA yield, mapping efficiency, and differentially expressed genes (DEGs) for the two methods (tape-strip/biopsy) and presence of AD (AD/non-AD) were compared.

Tape-strips demonstrated a lower RNA yield (22 vs. 4596 ng) and mapping efficiency to known genes (28% vs. 93%) than biopsies. Gene-expression profiles of paired tape-strips and biopsies demonstrated a medium correlation (R2 = 0.431). Tape-strips and biopsies demonstrated systematic differences in measured expression levels of 6483 genes across both AD and non-AD samples. Tape-strips preferentially detected many itch (CCL3/CCL4/OSM) and immune-response (CXCL8/IL4/IL5/IL22) genes as well as markers of epidermal dendritic cells (CD1a/CD207), while certain cytokines (IL18/IL37), skin-barrier genes (KRT2/FLG2), and dermal fibroblasts markers (COL1A/COL3A) were preferentially detected by biopsies. Tape-strips identified more DEGs between AD and non-AD (3157 DEGs) then biopsies (44 DEGs). Tape-strips also detected higher levels of bacterial mRNA than biopsies.

This study concludes that tape-strips and biopsies each demonstrate respective advantages for measuring gene-expression changes in AD. Thus, the specific skin layers and genes of interest should be considered before selecting either method.

The skin barrier is vital for protection against environmental threats including insults caused by skin-resident microbes. Dysregulation of this barrier is a hallmark of atopic dermatitis (AD) and ichthyosis, with variable consequences for host immune control of colonizing commensals and opportunistic pathogens. While Malassezia is the most abundant commensal fungus of the skin, little is known about the host control of this fungus in inflammatory skin diseases.

In this experimental study, MC903-treated mice were colonized with Malassezia spp. to assess the host-fungal interactions in atopic dermatitis. Additional murine models of AD and ichthyosis, including tape stripping, K5-Nrf2 overexpression and flaky tail mice, were employed to confirm and expand the findings. Skin fungal counts were enumerated. High parameter flow cytometry was used to characterize the antifungal response in the AD-like skin. Structural and functional alterations in the skin barrier were determined by histology and transcriptomics of bulk skin. Finally, differential expression of metabolic genes in Malassezia in atopic and control skin was quantified.

Malassezia grows excessively in AD-like skin. Fungal overgrowth could, however, not be explained by the altered immune status of the atopic skin. Instead, we found that by upregulating key metabolic genes in the altered cutaneous niche, Malassezia acquired enhanced fitness to efficiently colonise the impaired skin barrier.

This study provides evidence that structural and metabolic changes in the dysfunctional epidermal barrier environment provide increased accessibility and an altered lipid profile, to which the lipid-dependent yeast adapts for enhanced nutrient assimilation. Our findings reveal fundamental insights into the implication of the mycobiota in the pathogenesis of common skin barrier disorders.

When the ancestors of men moved from aquatic habitats to the drylands, their evolutionary strategy to restrict water loss is to seal the skin surface with lipids. It is unknown how these rigid ceramide-dominated lipids with densely packed chains squeeze through narrow extracellular spaces and how they assemble into their complex multilamellar architecture. Here it is shown that the human corneocyte lipid envelope, a monolayer of ultralong covalently bound lipids on the cell surface protein, templates the functional barrier assembly by partly fluidizing and rearranging the free extracellular lipids in its vicinity during the sculpting of a functional skin lipid barrier. The lipid envelope also maintains the fluidity of the extracellular lipids during mechanical stress. This local lipid fluidization does not compromise the permeability barrier. The results provide new testable hypotheses about epidermal homeostasis and the pathophysiology underlying diseases with impaired lipid binding to corneocytes, such as congenital ichthyosis. In a broader sense, this lipoprotein-mediated fluidization of rigid (sphingo)lipid patches may also be relevant to lipid rafts and cellular signaling events and inspire new functional materials.

Alterations in the secretion and composition of skin surface lipids (SSL) are closely associated with the development of acne. Lipidomics is a useful tool to analyse the SSL of different types of acne. Our previous study found that phosphatidylserine and triacylglycerols dominate SSL changes in male acne and infantile acne, respectively. However, skin surface lipids as well as specific lipids in female acne patients remain to be investigated.

To analyse and compare the SSL profile of acne women and healthy women and to discuss the involvement of differential lipids in acne development.

Systematic lipidomics approach (high-throughput UPLC-QTOF-MS technology in combination with multivariate data analysis methods) was used to analyse the variations of SSL between acne and healthy groups.

Analysis revealed significant differences in lipid content and composition between the two groups. Further analysis showed that levels of 13 individual lipids were significantly different and followed the same trend as the main class and subclasses. The largest individual contributor to the subgroup was triglycerides (TG) and phosphatidylinositol (PI). In addition, female acne patients exhibited reduced ceramide chain length (CCL) and increased levels of unsaturated fatty acids (UFAs), The changes of CCL in female acne are identical to male acne.

There was a significantly higher level of TG and PI in the SSL of female acne patients. A reduction in CCL and an increase in UFAs content might contribute to the reduced skin barrier function in acne patients. The results suggest that female acne may have different pathogenesis than male acne.

Skin barrier alterations play a crucial function in melasma development. Past researches have demonstrated variations in lipid content between the epidermis of melasma lesions and normal tissues, along with the varied expression of lipid-related genes in melasma. This study aimed to analyze the lipidome profiles of skin surface lipids (SSL) in patients with melasma before and after treatment to understand associated abnormalities.

Melasma was treated with tranexamic acid orally and hydroquinone cream topically. Disease was assessed using the Melasma Area and Severity Index (MASI), and the impact to life was evaluated with Melasma Quality of Life (MELASQoL) score. Epidermal melanin particles were observed using reflection confocal microscopy (RCM), whereas epidermal pigment and blood vessel morphology were observed using dermoscopy, and SSL samples were collected. Specific information regarding alterations in lipid composition was obtained through multivariate analysis of the liquid chromatography-mass spectrometry data.

After treatment, patients with melasma exhibited decreased MASI and MELASQoL scores (P < 0.001); RCM revealed reduced melanin content in the lesions, and dermoscopy revealed fewer blood vessels. Fifteen lipid subclasses and 382 lipid molecules were identified using lipidomic assays. The expression levels of total lipids, phosphatidylcholine, and phosphatidylethanolamine in the melasma lesions decreased after treatment (P < 0.05).

This study revealed alterations in the SSL composition after effective melasma treatment, suggesting a compensatory role for lipids in melasma barrier function. The mechanism involving SSL and the lipid barrier, which influences melasma's occurrence, needs further elucidation.

Atopic dermatitis is a multi-pathogenic disease characterized by chronic skin inflammation and barrier dysfunction. Therefore, improving the skin's ability to form an epidermal barrier and suppressing the production of cytokines that induce type 2 inflammatory responses are important for controlling atopic dermatitis symptoms. (-)-Blebbistatin, a non-muscle myosin II inhibitor, has been suggested to improve pulmonary endothelial barrier function and control inflammation by suppressing immune cell migration; however, its efficacy in atopic dermatitis is unknown. In this study, we investigated whether (S)-(-)-blebbistatin O-benzoate, a derivative of (-)-blebbistatin, improves dermatitis symptoms in a mite antigen-induced atopic dermatitis model using NC/Nga mice. The efficacy of the compound was confirmed using dermatitis scores, ear thickness measurements, serum IgE levels, histological analysis of lesions, and filaggrin expression analysis, which is important for barrier function. (S)-(-)-Blebbistatin O-benzoate treatment significantly reduced the dermatitis score and serum IgE levels compared to those in the vehicle group (p < 0.05). Furthermore, the histological analysis revealed enhanced filaggrin production and a decreased number of mast cells (p < 0.05), indicating that (S)-(-)-blebbistatin O-benzoate improved atopic dermatitis symptoms in a pathological model. In vitro analysis using cultured keratinocytes revealed increased expression of filaggrin, loricrin, involucrin, and ceramide production pathway-related genes, suggesting that (S)-(-)-blebbistatin O-benzoate promotes epidermal barrier formation. Furthermore, the effect of (S)-(-)-blebbistatin O-benzoate on type 2 alarmin cytokines, which are secreted from epidermal cells upon scratching or allergen stimulation and are involved in the pathogenesis of atopic dermatitis, was evaluated using antigens derived from mite feces. The results showed that (S)-(-)-blebbistatin O-benzoate inhibited the upregulation of these cytokines. Based on the above, (S)-(-)-blebbistatin O-benzoate has the potential to be developed as an atopic dermatitis treatment option that controls dermatitis symptoms by suppressing inflammation and improving barrier function by acting on multiple aspects of the pathogenesis of atopic dermatitis.