Female-pattern hair loss is common in obese women with polycystic ovary syndrome (PCOS), recently proposed as polyendocrine metabolic ovarian syndrome (PMOS) and is often associated with hypertriglyceridemia (TG), although the underlying mechanisms remain unclear. This study investigated how metabolic factors and androgens contribute to hair loss in female mice exposed to a high-fat diet (HFD). A controlled, parallel-group study using 8-week-old female C57BL/6 mice fed either an HFD (60% kcal fat) or a standard diet for 16 weeks. Mice were sacrificed at baseline and 4-week intervals for serial evaluation of metabolic, hormonal and skin changes (n = 6/group/time point). Hair loss was quantified from digital photographs using the ImageJ and further supported by histological examination. Circulating metabolic and hormonal profiles were measured. In dorsal skin, oxidative stress (malondialdehyde, MDA) and androgen-related markers-5-alpha-reductase type II (5αR2), dihydrotestosterone (DHT) and androgen receptor (AR)-were evaluated using immunohistochemistry, Western blot and enzyme-linked immunosorbent assay. From Week 12 onward, HFD-fed mice exhibited greater weight gain, pronounced dorsal hair thinning and elevated TG, insulin and free androgen index (FAI) levels. Skin MDA, 5αR2, DHT and AR levels also progressively increased. In the second experiment, 8-week-old female mice were assigned to four groups (n = 6/group): HFD with N-acetylcysteine (NAC), finasteride, spironolactone, or vehicle administered by oral gavage for 12 weeks. Compared with HFD-vehicle, antioxidant or anti-androgen co-treatment significantly lowered serum TG, tissue MDA and ameliorated hair thinning despite similar weight gain and 5αR2 levels. NAC reduced TG, FAI and decreased tissue MDA, DHT and AR. Finasteride lowered TG, MDA, DHT and AR, whereas spironolactone reduced TG and MDA. HFD-induced obesity exacerbates hair loss in female mice by enhancing oxidative stress and activating androgen signalling in the skin. Targeting these pathways, such as antioxidants and antiandrogens, may mitigate HFD-accelerated hair loss.

Cutaneous antimicrobial peptides (AMPs) are increasingly recognized for their multifaceted roles in skin disease and cancer, and thus application for therapeutic potential. Beyond their contributions to innate defence and the skin's microbiome, AMPs have been implicated in inflammatory skin conditions and cutaneous malignancies. Comprehensive summaries of AMPs' roles in skin cancer and related current clinical developments remain scarce, despite abundant emerging evidence of pro- and anti-tumour properties in other fields. This review provides a comprehensive discussion of AMPs, including dermcidin, psoriasin (S100A7), human cathelicidin (LL-37), RNase-7 and the human β-defensins, in the context of skin cancer research and clinical developments. These AMPs influence skin tumorigenesis through microbiome regulation, innate immune pathways and chronic inflammation, and although the mechanistic details are subject to scrutiny, several AMP-derived therapies, including LL-37 and LTX-315, have been developed for their potential in cutaneous oncology.

Dystrophic epidermolysis bullosa (DEB) is a rare, debilitating genodermatosis caused by loss-of-function variants in COL7A1, resulting in type VII collagen (C7) deficiency and defective anchoring fibrils, which are essential for dermal-epidermal adhesion. COL7A1 is a large gene, and C7 is synthesized by both keratinocytes and fibroblasts, and extracellularly secreted, where it forms a supramolecular network that stabilizes the dermal-epidermal junction. Human genotype-phenotype correlations suggest that residual C7 expression (~10% of normal levels) may confer a milder disease phenotype, whereas complete absence results in generalized skin fragility with scarring and systemic complications. Thus, restoring C7 expression remains a central therapeutic objective. Since the discovery of COL7A1, thousands of pathogenic variants have been described, including amino acid substitutions in the triple-helical domain that allow partial C7 function, whereas null alleles are associated with severe phenotypes. Gene- and cell-based strategies have evolved to address the large COL7A1 size and delivery challenges. Ex vivo gene/cell therapies (keratinocytes or fibroblasts engineered to express COL7A1) have demonstrated partial, wound-specific C7 restoration but with durability limitations, as grafted cells may be outcompeted or lose transgene expression over time; select patients show sustained anchoring fibril formation and improved wound healing; however, long-term outcomes remain variable. In vivo topical gene therapy has achieved clinically meaningful wound closure in DEB, illustrating a paradigm shift toward accessible and patient-friendly therapeutic approaches, albeit with real-world considerations on durability and wound recurrence. A multidisciplinary framework integrating EB expert centers, drug-delivery pharmacy services, wound management, and patient-support programs can further enhance treatment access and adherence. General factors such as nutritional status, infection and comorbidities also influence both wound healing and the response to gene therapy. Revertant mosaicism offers a natural gene-therapy substrate: cultured epidermal autografts derived from revertant patches have yielded substantial, yet heterogeneous, epithelization, with outcomes contingent on revertant cell proportion and culture fidelity. Collectively, these advances highlight the emerging potential of gene- and cell-based therapies to achieve durable disease modification in DEB.

Repetin (RPTN) is a member of the fusion S100 protein family encoded within the epidermal differentiation complex. Although genetic studies have revealed that RPTN is a susceptibility gene for atopic dermatitis (AD), its biological function remains poorly understood. In this study, we investigated the role of RPTN in epidermal homeostasis and inflammatory skin diseases. We examined RPTN expression in normal skin, inflammatory skin diseases, and differentiated normal human keratinocytes (NHKs). Functional analyses were performed using RPTN knockdown (KD) NHK and three-dimensional (3D) skin-equivalent models. Epidermal barrier function was assessed using a lucifer yellow permeability assay, and cytokine-mediated regulation of RPTN expression was evaluated using 3D atopic dermatitis (AD) and psoriasis models. RPTN was primarily expressed in the granular layer of the normal epidermis and increased with keratinocyte differentiation. In the 3D skin-equivalent model, RPTN deficiency impaired epidermal barrier function and induced the expression of differentiation-related genes, including FLG, IVL, TGM1, CLDN1, KLK7, ALOX12, and TCHHL1. Notably, RPTN knockdown significantly increased IL-25 expression. RPTN expression was elevated in chronic atopic dermatitis (AD) lesions and in hypergranular epithelia of psoriasis vulgaris, lichen planus, and epidermolytic ichthyosis. In a 3D AD model, IL-4 and IL-13 significantly induced RPTN expression. These findings indicate that RPTN contributes to maintaining epidermal barrier homeostasis and suggest that it may be associated with regulating inflammatory responses.

Cutaneous lupus erythematosus (CLE) encompasses a heterogeneous group of autoimmune skin manifestations that often overlap clinically with other inflammatory dermatoses, particularly rosacea. While histopathology remains the gold standard, its invasiveness limits routine and longitudinal use. Line-field confocal optical coherence tomography (LC-OCT) is an emerging non-invasive imaging modality capable of providing real-time, near-histological resolution of skin architecture. In this single-center cross-sectional observational study, 45 patients (30 CLE: 16 acute, 5 subacute, 9 chronic; 15 rosacea) underwent LC-OCT imaging of active lesions. Images were independently evaluated using predefined criteria reflecting histopathological features. LC-OCT identified key histopathological correlates of CLE in vivo. Interface dermatitis features (including dermoepidermal junction disruption, basal cell vacuolization and band-like inflammatory infiltrate) were highly prevalent in ACLE and SCLE, while chronic CLE was characterized by epidermal atrophy, hyperkeratosis, fibrosis and adnexal destruction. In contrast, rosacea exhibited a vascular and folliculocentric pattern with frequent peri-adnexal inflammation and Demodex infestation, without interface changes. Interobserver agreement was substantial to excellent for most criteria. In the ACLE versus rosacea comparison, interface dermatitis features like band-like DEJ infiltrate, DEJ disruption, basal vacuolization and apoptotic bodies were associated with ACLE. Conversely, rosacea exhibited a vascular-folliculocentric profile with peri-infundibular infiltrates and Demodex mites. In conclusion, LC-OCT enables non-invasive visualization of disease-specific microarchitectural patterns in CLE, reflecting both inflammatory and chronic remodelling changes. In this pilot study, it shows potential in differentiating CLE from rosacea and may support diagnosis, staging and treatment monitoring in clinical practice. Larger, multicenter studies are required to confirm the role of LC-OCT in the non-invasive diagnosis of CLE.

Nevus-associated melanoma (NAM) is histologically defined by coexisting nevus and melanoma components, yet the nevus component is frequently not visible on dermoscopy. We performed a retrospective, single-centre observational study including histologically diagnosed NAMs (2011-2024). Dermoscopic images were assessed independently by two readers. Histopathology was systematically revised to quantify nevus proportion, size, and depth. Univariate and multivariable logistic regression evaluated associations with (a) invasive vs. in situ NAM and (b) dermoscopically visible vs. non-visible nevus component. Among 340 NAMs, 36.8% were in situ and 63.2% invasive. A dermoscopic nevus was visible in 45.6%. In multivariable analysis, nevus visibility under dermoscopy was independently associated with histopathologic features such as larger nevus size, particularly 2.1-4 mm (OR 2.5, 95% CI 1.3-4.6), 4.1-10 mm (OR 3.7, 95% CI 2.0-7.0), and > 10 mm (OR 5.3, 95% CI 1.4-20.0), whereas deep nevus location (OR 0.3, 95% CI 0.2-0.5) and ulceration (OR 0.2, 95% CI 0.1-0.6) reduced visibility. Invasive NAM was independently associated with a visible nevus component under dermoscopy (OR 2.5, 95% CI 1.7-3.7), shiny white structures (OR 5.0, 95% CI 2.6-9.4), negative pigment network (OR 1.9, 95% CI 1.2-3.2), and blue-white veil (OR 8.3, 95% CI 4.5-15.4), whereas atypical pigment network and melanoma pigmentation were inversely associated with invasion. Dermoscopic nevus visibility in NAM is mainly determined by nevus size and depth, while melanoma-related changes, particularly ulceration, can obscure the nevus component. Dermoscopic markers of invasiveness should prompt timely management even when an associated nevus is suspected.

Alopecia areata (AA) is an autoimmune hair disorder characterized by interferon-gamma (IFN-γ)-driven inflammation and collapse of hair follicle immune privilege. Although Janus kinase (JAK) inhibitors are effective, incomplete or delayed responses remain common. Minoxidil is frequently combined with JAK inhibitors in clinical practice, yet its immunomodulatory mechanisms in AA are unclear. We investigated the effects of minoxidil sulfate (MXS) on inflammatory signalling, immune privilege-associated features and mitochondrial stress responses, and evaluated whether MXS enhances the anti-inflammatory effects of the JAK inhibitor baricitinib. Clinical observations of patients receiving combination therapy were descriptively assessed. Mechanistic studies were conducted in human outer root sheath (ORS) cells stimulated with IFN-γ and polyinosinic:polycytidylic acid to model the AA inflammatory microenvironment. Representative clinical observations suggested accelerated hair regrowth after addition of oral minoxidil to baricitinib. In inflamed ORS cells, MXS enhanced baricitinib-mediated suppression of STAT1 phosphorylation and IFN-γ-inducible chemokines (CXCL9, CXCL10, CXCL11). MXS also exerted baricitinib-independent anti-inflammatory effects by inhibiting STAT1 and STAT3 activation. Furthermore, MXS reduced inflammatory induction of MHC class I expression and partially restored insulin-like growth factor-1 expression. MXS attenuated cytosolic and mitochondrial reactive oxygen species accumulation, mitochondrial DNA damage and loss of mitochondrial membrane potential, accompanied by suppression of NOX1 and NOX4 expression. These findings suggest that MXS modulates inflammatory signalling, preserves immune privilege-associated features and protects mitochondrial integrity, providing a mechanistic rationale for adjunctive use with JAK inhibitors without additional systemic immunosuppression.

Translating hidradenitis suppurativa (HS) genetic susceptibility into actionable targets remains challenging, as most genome-wide association study loci lie in non-coding regions and tissue-level transcriptomics cannot easily distinguish causal drivers from secondary inflammation. In this study, we aimed to prioritize plasma proteins whose genetically predicted levels are causally associated with HS risk and to localize them within human skin at single-cell resolution. We performed two-sample Mendelian randomization (MR) using cis-pQTL instruments for 2923 plasma proteins from the UK Biobank Pharma Proteomics Project against HS summary statistics from FinnGen R12. Following multiple-testing correction and Bayesian colocalization with a prior-sensitivity grid, the intersection of false-discovery rate (FDR)-significant MR with colocalization evidence (PP.H4 ≥ 0.5) yielded three putative protective candidates: TNFRSF6B (OR = 0.748, 95% CI 0.666-0.840; PP.H4 = 0.648), FCRL2 (OR = 0.896, 95% CI 0.819-0.979; PP.H4 = 0.550), and APOD (OR = 0.789, 95% CI 0.647-0.963; PP.H4 = 0.503). All sensitivity MR tests were concordant. Single-cell transcriptomic analysis localized FCRL2 and APOD to specific cell populations. FCRL2 was predominantly expressed in B cells and NK cells, while APOD showed multi-cellular expression across cornified keratinocytes, macrophages, and dendritic cells. Furthermore, TNFRSF6B was below the skin detection threshold, supporting its biological role as a circulating decoy receptor. Together, our integrated proteogenomic and single-cell approach prioritizes TNFRSF6B, FCRL2, and APOD as putative protective plasma proteins for HS, with TNFRSF6B emerging as the most genetically robust candidate for future translational follow-up.

Head and neck dermatitis (HND) is a distinct clinical phenotype of atopic dermatitis (AD). While Malassezia sensitisation and elevated Malassezia-specific IgE antibody (MSIA) levels have been documented in HND patients, the relationship between MSIA levels and disease severity remains controversial. The primary aim of our study was to evaluate whether MSIA levels correlate with the severity of HND. This retrospective observational study was conducted at a single tertiary center and included 121 patients with AD. Laboratory data included serum MSIA, house dust mite (HDM)-specific IgE and total IgE levels. Clinical severity was measured using the global Eczema Area and Severity Index (EASI) and partial HND EASI scores. We introduced a novel metric, the 'relative HND severity score', defined as the HND EASI score divided by the global EASI score. Spearman's Rho correlation analyses were used to examine the correlations between different IgE levels and severity scores. The HND EASI score demonstrated significant positive correlations with MSIA (r = 0.569, p < 0.001) and both HDM-specific antibodies: D1 (r = 0.247, p = 0.007) and D2 (r = 0.267, p = 0.004). The relative HND severity score was significantly positively correlated with MSIA (r = 0.353, p < 0.001), but not with HDM-specific antibodies (D1, p = 0.985; D2, p = 0.974). Age-stratified subgroup analyses revealed significant positive correlations between MSIA and both absolute (r = 0.591, p < 0.001) and relative HND severity (r = 0.344, p = 0.002) only in the adult cohort. In conclusion, serum MSIA levels significantly correlate with the clinical severity of HND in Korean AD patients. This association is most clearly observed in the adult population.

Psoriasis is a chronic inflammatory skin disorder driven by systemic immune dysregulation and recent studies have implicated the gut-skin axis in its pathogenesis. However, the specific role of individual gut microbes remains poorly understood. In this study, the impact of Prevotella copri (P. copri) on psoriasis development was examined and the underlying mechanisms were investigated. In an imiquimod (IMQ)-induced mouse model, oral administration of P. copri exacerbated skin inflammation, increased epidermal thickness, promoted neutrophil infiltration and aggravated disease severity. In vitro, stimulation with P. copri enhanced keratinocyte proliferation and pro-inflammatory responses, thereby activating co-cultured neutrophils. These effects were associated with activation of the NF-κB signalling pathway, as evidenced by increased phosphorylation of p65 and upregulation of inflammasome components. The inhibition of NF-κB signalling attenuated P. copri-induced keratinocyte hyperproliferation, neutrophil activation and inflammatory cytokine production. Our findings suggest that P. copri promotes psoriasis progression via NF-κB-mediated keratinocyte-neutrophil crosstalk, potentially through a gut-derived systemic inflammatory mechanism. Targeting the gut-skin axis and NF-κB pathway may offer new therapeutic opportunities for psoriasis.

Human-derived exosomes show promise for hair loss treatment but may pose safety concerns, including inflammatory responses and pathogen transmission. Here, we investigated whether plant-derived exosomes, whose isolation can be standardized, and which show lower compositional complexity and no immunogenicity, represent a valid alternative. We isolated and characterized exosome-like nanovesicles from the Ashwagandha plant (Ash-ELNs), which is traditionally used to relieve stress, and pre-clinically explored their hair growth-promoting potential. Multi-omic approaches demonstrated low variations in the content of seven different Ash-ELN preparations, and cellular vesicle uptake was confirmed in human dermal fibroblasts (HDFs). In a scratch assay of human dermal papilla fibroblasts (HDPCs), Ash-ELNs significantly increased the production/secretion of the hair growth promoters VEGF-A, PLGF1, FGF2 and LIF. Application of Ash-ELNs to healthy human microdissected hair follicles significantly prolonged anagen and increased hair shaft production, while hair matrix keratinocyte proliferation and -apoptosis remained unaltered. Ash-ELNs significantly upregulated VEGF-A protein expression in the bulb mesenchyme, corroborating our in vitro results. Finally, Ash-ELNs promoted tubulogenesis in an HDF-human umbilical vein endothelial cell (HUVEC) assay, suggesting VEGF-A-induced angiogenesis as a possible mechanism underlying the anagen promoting effect of Ash-ELN. Thus, Ash-ELN treatment offers a novel adjuvant strategy or non-drug agent to reduce hair shedding.

The diagnosis of an ectodermal dysplasia (ED) is often made by dermatologists. Some of the more than 50 distinct ectodermal dysplasias, however, are still largely unknown and their pathogenesis is poorly understood. Since we recently discovered that variants of the Interferon Regulatory Factor 6 (IRF6) gene IRF6 may cause ED, we have further investigated the link between this gene and maldevelopment of tissues originating from the embryonic ectoderm. Disease characterization in two previously reported subjects and one newly identified patient (mosaic status) included systematic clinical and genetic evaluation, assessment of all available patient records and dental radiographs, hearing tests and immunostaining of skin samples. Structural models of native and mutant IRF6 were analysed to elucidate the pathogenesis. IRF6-associated ED, a combination of natal teeth (irregularly), absent sweat glands, hidradenitis suppurativa-like symptoms, onychodysplasia, agenesis of numerous deciduous and permanent teeth, and sensorineural hearing impairment, was linked to amino acid substitutions in a region between the DNA-binding domain and the protein-binding domain of IRF6, which has not yet been assigned a function. Genotype-phenotype correlations from a total of five patients and immunohistochemical data support the assumption that IRF6-associated ED is based on a gain-of-function mechanism. Thus, IRF6 variants are not only the cause of Van der Woude syndrome and popliteal pterygium syndrome, two diseases with cleft lip/palate as common features, but are most likely responsible also for a new, challenging syndrome without orofacial clefting. Our results facilitate accurate and early diagnosis in affected individuals and may pave the way for specific treatment.

Vitiligo is an autoimmune pigmentary disorder characterized by progressive melanocyte loss and unpredictable activity. Objective of disease activity remains challenging, particularly in lesions with subtle clinical changes Cellular-resolution full-field optical coherence tomography (CRFF-OCT) enables non-invasive, high-resolution, histology-like visualization of skin microstructure. This study evaluated the feasibility of integrating CRFF-OCT with machine learning-assisted quantitative analysis for imaging-based characterization of active and stable vitiligo lesions. Fifty patients with non-segmental vitiligo were prospectively enrolled (2021-2022). CRFF-OCT imaging was performed on lesional, perilesional, and normal-appearing skin within the same anatomical region. Quantitative features describing epidermal structure, dermal-epidermal junction (DEJ) morphology, and pigment-associated reflectivity were extracted. A machine learning-assisted computer-aided detection (CADe) framework incorporating 13 features was developed for image-level classification of lesion activity. CRFF-OCT imaging demonstrated distinct microstructural patterns between active and stable lesions. Basal epidermal pigment-associated reflectivity was significantly lower in stable lesions compared with active lesions (9.94% ± 10.06% vs. 21.84% ± 11.08%), with corresponding differences in lesion-to-normal reflectivity ratios (0.21 vs. 0.56). Quantitative analysis revealed significant differences in epidermal thickness, DEJ associated reflectivity, inter-layer contrast, and reflectivity heterogeneity. Among the 13 extracted features, 9 differed significantly between groups and were incorporated into classification models. The CADe framework achieved a maximum image-level classification accuracy of 80.6% using a support vector machine model. These findings demonstrate the feasibility of CRFF-OCT-based quantitative imaging for objective characterization of vitiligo lesion status and support its potential role in disease activity assessment and longitudinal monitoring.

Bullous pemphigoid (BP) is an autoimmune blistering disease with an increasing incidence in recent years; however, the underlying immune regulatory mechanisms remain largely unclear. As a critical signalling hub linking innate and adaptive immunity, stimulator of interferon genes (STING) has recently been implicated in the pathogenesis of various autoimmune diseases and may regulate tissue inflammation and immune homeostasis through modulation of CD4[+] T cell responses. In this study, we found that STING expression was significantly increased in lesional skin tissues from patients with BP compared with healthy controls. Transcriptomic analysis further revealed that differentially expressed genes in peripheral blood CD4[+] T cells from BP patients were primarily enriched in the JAK-STAT signalling pathway, T cell activation and differentiation, and type I interferon (IFN-I)-related pathways. Pharmacological inhibition of STING markedly attenuated the aberrant activation of these signalling pathways. Moreover, qRT-PCR analysis confirmed that the mRNA levels of STING1, JAK1, and CXCR5 were significantly elevated in BP patients, whereas treatment with the STING inhibitor C176 suppressed the expression of these molecules. Collectively, our findings suggest that STING may contribute to BP immunopathogenesis by regulating the JAK-STAT signalling axis and promoting abnormal CD4[+] T cell activation and differentiation, providing new insights into the molecular mechanisms underlying BP and identifying potential therapeutic targets.