Granular parakeratosis (GP) is an uncommon keratinization disorder that predominantly affects intertriginous areas and may clinically mimic atopic dermatitis or psoriasis. Histologically, GP is characterized by compact hyperkeratosis, parakeratosis, and retention of keratohyalin granules within the stratum corneum, although its histopathological spectrum is heterogeneous. Previous studies have consisted mainly of case reports, while mechanistic investigations remain limited, and whether GP represents a purely cornification-related abnormality is unclear. During and after the coronavirus disease 2019 (COVID-19) pandemic, increased use of benzalkonium chloride (BAC)-containing laundry disinfectants coincided with more patients presenting with recurrent erythema and scaling that responded poorly to conventional treatment, prompting renewed attention to this disease. We performed single-cell RNA sequencing of lesional skin from three patients with GP and matched skin samples from three healthy controls, followed by keratinocyte subclustering, pseudotime analysis, and cell-cell communication analysis. Key findings were further validated by immunofluorescence in an independent cohort of four patients with GP and three healthy controls. HaCaT cells were exposed to BAC and analyzed by the Cell Counting Kit-8 (CCK-8) assay and bulk RNA sequencing. Single-cell analysis revealed the expansion of inflammatory keratinocytes in GP lesions. Pathway enrichment showed the activation of innate immune and antimicrobial responses and dysregulation of keratinocyte differentiation. S100A8/S100A9 were increased in GP keratinocytes and validated at the protein level. BAC induced interleukin-1 (IL-1)-related inflammatory activation and cellular stress responses, suggesting that GP is an exposure-associated inflammatory epidermal differentiation disorder.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by epidermal barrier dysfunction, immune dysregulation, and increased oxidative stress. The current treatment strategies include topical corticosteroids, calcineurin inhibitors, and systemic immunomodulators. However, long-term use of steroids and other immunomodulators has unwanted side effects, and therefore recent interest has shifted towards complementary natural therapeutic approaches. Several studies indicate that natural plant-based antioxidants may help prevent AD. Specifically, a few studies demonstrated the significance of fat-soluble vitamins (A, D, E, and K) in controlling AD, owing to their strong roles in antioxidant defense, immune regulation, and maintenance of epidermal barrier integrity. In this review, we discussed recent evidence demonstrating the significant biological and therapeutic roles of fat-soluble vitamins in AD. We also discussed how vitamins A, D, E, and K may influence multiple mechanisms involved in AD pathogenesis and their potential as adjuvant therapy. Based on limited preclinical and clinical data, additional well-designed mechanistic and clinical trials are needed to establish their therapeutic efficacy in treating AD.

Receptor-interacting protein kinase 2 (RIPK2) is a critical mediator of the immune system leading to production of pro-inflammatory cytokines. Its role in the pathogenesis of atopic dermatitis (AD) has not been defined. This work aims to assess RIPK2 expression in the skin in AD and to evaluate the association with Th1-, Th2-, and Th17-related cytokine expression in lesional skin. AD patients' skin biopsies and healthy controls were collected. An OPAL multiplex immunohistochemistry method was used to simultaneously detect TNF-α, IL-4, IL-13 and IL-17 in CD4[+] RIPK2[+] and CD4[+] RIPK2[-] T cells. Quantitative image analysis was performed, and group comparisons were made using non-parametric Mann-Whitney tests. Our results show that CD4[+]RIPK2[+] cells were significantly abundant in AD skin, with mark increased expression of Th1, Th2, and Th17 cytokines simultaneously. However, CD4[+] RIPK2[-] T cells in AD overexpress TNFa without elevated Th2 cytokines, and IL-17[+] cells were only marginally increased. In conclusion RIPK2 expression is upregulated in infiltrating CD4[+] T cells in AD skin, with a mixed Th1/Th2 cytokine profile, suggesting that enhanced RIPK2 signaling contributes to the immune dysregulation in adult AD. These findings identify RIPK2 as a potential marker of Th1/Th2-high immune endotypes in AD and as a possible therapeutic target for intervention.

Inflammatory skin diseases, including atopic dermatitis (AD), psoriasis, diabetic wounds, and photoaging, represent major public health challenges due to their high prevalence, chronic recurrence, and substantial disease burden. Current treatments, such as glucocorticoids, calcineurin inhibitors, and biologics, are often constrained by limited efficacy, long-term adverse effects, or high costs, highlighting the need for safer and more accessible therapeutic strategies. Cerium oxide nanoparticles (CeO2 NPs) have attracted increasing attention because of their reversible Ce[3+]/Ce[4+] redox cycling and multiple enzyme-mimetic activities. This review examines the synthesis strategies and structure-activity relationships of CeO2 NPs, and discusses their antioxidant, anti-inflammatory, immunomodulatory, antimicrobial, and proangiogenic mechanisms in inflammatory skin microenvironments. We further evaluate their applications in AD, psoriasis, diabetic wounds, and photoaging, and summarize advanced delivery approaches involving structural functionalization, biomimetic surface modification, and formulation hybridization. Key translational challenges, including long-term safety, degradability, manufacturing consistency, and disease-specific applicability, are also discussed. Finally, we propose a "5D" framework for next-generation CeO2-based nanomedicines, integrating disease-specific design, degradability, data-driven optimization, device integration, and digital health interfacing.

Atopic dermatitis is a common inflammatory skin disease affecting up to 10% of adults. Whether atopic dermatitis exhibits a strong systemic inflammatory signature remains debated. We characterized peripheral whole-blood alterations in adults with moderate-to-severe atopic dermatitis undergoing treatment with dupilumab or baricitinib therapy. Blood samples were collected at weeks 0, 4, and 16. Whole-blood proteins were measured using Olink, transcriptomic profiling was performed by RNA sequencing, and torque teno virus plasma levels were quantified by qPCR. During targeted atopic dermatitis therapy with dupilumab or baricitinib, clustering of samples based on gene expression levels showed no separation by time or treatment, with only a limited number of differentially expressed genes. Proteomic changes were similarly modest; however, treatment was consistently associated with decreased CCL17/TARC levels. Teno torque virus plasma load remained stable throughout therapy, indicating preserved immunocompetence. These findings suggest that the dominant inflammatory processes in atopic dermatitis may be largely tissue-restricted, supporting the use of peripheral biomarkers for pragmatic monitoring rather than mechanistic discovery.

Atopic dermatitis (AD) is characterized by pruritus and epidermal barrier dysfunction. Tapinarof, a therapeutic aryl hydrocarbon receptor (AHR)-modulating agent, is clinically effective in AD, but its mechanisms in allergen-driven models remain unclear. We evaluated tapinarof in a Dermatophagoides farinae (Df)-induced murine model of AD, focusing on AHR-mediated barrier restoration. AD-like dermatitis was induced in female NC/Nga mice, followed by daily topical tapinarof or betamethasone for four days. Disease severity, transepidermal water loss (TEWL), histopathology, and gene/protein expression were assessed. Tapinarof significantly reduced dermatitis scores and TEWL and, unlike betamethasone, preserved epidermal architecture without suppressing ear swelling. Tapinarof upregulated the AHR-responsive genes Cyp1a1 and Nqo1 and induced Ovol1, an epidermal differentiation-associated transcription factor, with increased CYP1A1, NRF2, NQO1, and OVOL1 protein expression. Tapinarof markedly increased filaggrin (FLG)- and loricrin (LOR)-positive areas in lesional skin compared with vehicle (FLG: 11.3% vs. 3.1%; LOR: 18.9% vs. 3.9%; both p < 0.05), restoring FLG to a level comparable to the no-treatment control, while LOR significantly exceeded it. These findings indicate that tapinarof may restore skin barrier function in allergen-induced AD via AHR-NRF2 and AHR-OVOL1 signaling, supporting its potential as a steroid-sparing topical therapy for long-term AD management.

Background: Appropriate diagnostic testing is essential to quality pediatric allergy care, affecting diagnostic accuracy, treatment decisions, resource use, and patient outcomes. This study aimed to develop evidence-based recommendations for specialist consultations and diagnostic investigations in children with food allergies, eosinophilic gastrointestinal diseases, urticaria, angioedema, and atopic dermatitis. Methods: A multidisciplinary panel convened for the Italian National Institute of Health formulated and prioritized clinical questions using the PICO framework and structured expert consensus. A systematic review of the literature from 2015 to 2026 informed the recommendations, with certainty of evidence assessed using GRADE methodology. Results: In food allergy, sensitization tests alone are insufficient for diagnosis, while oral food challenges remain central to diagnostic confirmation. Endoscopic biopsies are essential for diagnosing eosinophilic gastrointestinal diseases. In chronic urticaria, specialist consultation is recommended, whereas routine allergy testing should be avoided without a suggestive clinical history. In angioedema, distinguishing histaminergic from bradykinin-mediated forms is critical, with targeted laboratory testing for hereditary or acquired conditions. In atopic dermatitis, standardized severity assessment should guide management and consideration of biologic therapies, while patient and family education represent key components of care. Conclusions: These recommendations provide a framework for standardized pediatric allergy diagnostic pathways, aiming to improve quality and equity of care while reducing unnecessary investigations and optimizing healthcare resource use.

Recent advances in cutaneous neuroimmunology have substantially expanded our understanding of inflammatory skin diseases, revealing an intricate bidirectional network linking peripheral sensory neurons, resident immune cells, and structural skin components. Among the mediators orchestrating this communication, substance P (SP) and mast cells have emerged as pivotal regulators connecting neuronal activation with immune responses, vascular dysfunction, chronic inflammation, and persistent pruritus. Beyond the canonical neurokinin-1 receptor (NK1R), the identification of the Mas-related G protein-coupled receptor X2 (MRGPRX2) has fundamentally reshaped mast-cell biology by establishing an IgE-independent pathway of neuropeptide-induced activation. This narrative review examines the molecular mechanisms underlying the mast cell-SP neuroimmune axis and discusses its contribution to the pathogenesis of allergic contact dermatitis and atopic dermatitis. Unlike the traditional approach, which primarily considers atopic dermatitis as the reference model for cutaneous neuroimmune interactions, allergic contact dermatitis may provide a useful model for examining how neuroimmune amplification integrates with delayed T-cell-mediated inflammation. These concepts are subsequently applied to atopic dermatitis, where they operate within the broader context of type 2 inflammation, epidermal barrier dysfunction, and chronic pruritus. Rather than replacing classical immunopathogenic models, this emerging neuroimmune perspective complements them by identifying bidirectional communication between sensory neurons and mast cells as a dynamic amplifier of adaptive immune responses. This integrated perspective not only provides a unifying interpretation of inflammatory dermatitis but also offers a conceptual basis for exploring similar neuroimmune mechanisms across other immune-mediated skin disorders and for generating future mechanism-based therapeutic hypotheses.

Single-cell RNA sequencing (scRNA-seq) studies are frequently organized around comparisons-disease versus control, treatment response, or genetic perturbation-yet biological interpretation still depends on integrating multiple independent downstream analyses for differential expression, functional enrichment, regulatory network inference, and cell-cell communication analysis. Applying these tools consistently across comparisons typically requires substantial custom scripting, and their heterogeneous outputs must be manually harmonized before the results can be compared or reported together. We present scFlowReport, a lightweight, configuration-driven workflow that propagates a single user-defined comparison across cell-level and sample-aware pseudobulk differential expression, over-representation and ranked functional enrichment, transcription-factor regulon export for SCENIC, and group-resolved LIANA cell-cell communication analysis, starting from an already annotated Seurat object. The workflow automatically compiles complementary downstream results into standardized figures, summary tables, and a self-contained static HTML report that can be readily inspected and shared without requiring a persistent server. Application of scFlowReport to a publicly available Atopic Dermatitis scRNA-seq dataset demonstrated its utility by enabling researchers to obtain complementary biological evidence from multiple established downstream analyses. By coordinating complementary downstream analyses under a shared comparison framework, scFlowReport provides a practical and reproducible workflow for systematic interpretation of comparative single-cell transcriptomic data.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease characterized by epidermal barrier dysfunction, immune dysregulation, microbial imbalance, and severe pruritus. Emerging evidence establishes that barrier disruption is a central pathogenic driver capable of initiating inflammatory signaling, neuroimmune activation, and chronic disease instability. This understanding has shifted therapeutic paradigms toward barrier-directed strategies aimed at restoring epidermal resilience. This narrative review evaluates the mechanistic and clinical evidence surrounding isosorbide fatty acid diester molecules-specifically isosorbide dicaprylate (IDC) and isosorbide di-(linoleate/oleate) (IDL)-as a barrier-first approach for AD management. Early in vitro and ex vivo investigations demonstrated that IDC significantly improves epidermal hydration, transepidermal water loss, and the expression of barrier-associated genes linked to epidermal integrity. Subsequent studies showed that IDL expands these effects through coordinated regulation of keratinocyte differentiation, lipid homeostasis, and inflammatory stress pathways. Furthermore, recent mechanistic data highlight synergistic anti-inflammatory and pruritus-modulating effects involving TRPA1-, TRPV3-, and TSLP-associated pathways, while preserving tissue integrity under cytokine-induced stress. Clinically, these findings are supported by randomized studies in pediatric and adult cohorts demonstrating significant reductions in pruritus, favorable Eczema Area and Severity Index (EASI) responses, decreased topical corticosteroid dependence, and a reduction in the relative abundance of Staphylococcus aureus. Collectively, these findings support a barrier-first therapeutic framework in which restoration of epidermal resilience may beneficially influence multiple interconnected pathways involved in atopic dermatitis.

Background: Portulaca oleracea L. (POL) has anti-inflammatory and immunomodulatory activities, but its mechanism against atopic dermatitis (AD) remains incompletely understood. Methods: 2,4-dinitrofluorobenzene (DNFB)-induced AD mice were treated orally with POL or dexamethasone for 14 days. We evaluated skin lesions, scratchizng, serum IgE, histopathology, inflammatory cytokines, skin-barrier genes, JAK/STAT phosphorylation, and fecal metabolites. Results: POL alleviated skin lesions and pruritus, reduced serum IgE concentrations, attenuated epidermal hyperplasia and inflammatory-cell and mast-cell infiltration, and restored keratinocyte architecture. It decreased IL-4, IL-13, and IL-31 expression, increased filaggrin and loricrin expression, and inhibited JAK1, STAT1, and STAT3 phosphorylation. Untargeted metabolomics showed that POL mainly regulated unsaturated fatty acid and steroid hormone biosynthesis and restored levels of anti-inflammatory and antiallergic metabolites, including (±)18-HEPE, docosahexaenoyl ethanolamide, and dehydroepiandrosterone. Conclusions: These findings indicate that POL ameliorates AD by suppressing Th2 inflammation through JAK1/STAT3 signaling, correcting lipid-metabolic disturbances, and restoring skin barrier integrity.

Background/Objectives: Chronic pruritus of unknown origin (CPUO) is mechanistically poorly resolved, and its relationship to atopic dermatitis (AD) is unclear. We asked how much apparent separation survives removal of leakage. Methods: Public bulk skin data (GSE237920; four healthy, four AD, four CPUO) were analyzed by differential expression and an XOmiVAE-inspired latent model, with public single-cell and atlas resources for context. Every label-dependent step was then re-executed inside each cross-validation fold, with label permutation and 1000 bootstraps. A frozen composite niche score was applied unchanged to prurigo nodularis (GSE210854) and AD (GSE174582) cohorts. Results: Fully nested, the latent classifier separated CPUO from healthy skin (AUC 1.000; permutation p = 0.020) but not from AD (0.741; p = 0.140); randomized labels also reached 1.00. The composite score reached 0.919 against healthy skin but did not exceed its null (p = 0.086). Six genes recurred in ≥80% of bootstraps, five within the signature. Cell-type-restricted blood analysis recovered CPUO-associated monocyte CCL3 upregulation. In both validation cohorts, the frozen score was reduced, not elevated, in lesional skin. Conclusions: CPUO skin differs from healthy skin and occupies the low-inflammatory, epidermal-stress-dominated pole opposite lesional inflammatory skin, but cannot be robustly separated from AD at twelve samples.

Atopic dermatitis (AD) is a chronic inflammatory disease characterized by recurrent bacterial infections that cause pruritus, erythema, xerosis and thickening. Cajanus cajan root extract prepared with 95% ethanol (EECR95) has been shown to possess antioxidant, anti-inflammatory, and antibacterial properties in previous studies. This study aimed to evaluate EECR95's ability to improve AD by inhibiting methicillin-resistant Staphylococcus aureus (MRSA) growth and reducing inflammation. This study found EECR95 effectively inhibits MRSA growth (IC50 = 103.74 μg/mL) and reduces pro-inflammatory cytokine production in an MRSA-keratinocyte-macrophage model. LC/MS/MS analysis revealed the presence of active compounds-flavonoids, isoflavones, and flavonoid glycosides, highlighting EECR95's potential in improving atopic dermatitis in vitro.