Experimental Dermatology

Skin pigmentation relies on the coordinated regulation of melanin production and dendritic morphology to ensure effective pigment distribution. While staurosporine is widely used as a proapoptotic agent in malignant cells, its effects on normal human melanocytes have not been fully characterized. Here, we investigated the impact of staurosporine on melanocyte biology and identify it as a potent inducer of non-canonical melanocyte maturation at sub-cytotoxic concentrations. In primary human neonatal melanocytes, staurosporine treatment enhances melanogenesis and promotes pronounced dendritic remodeling, leading to functional maturation distinct from its apoptotic effects in melanoma cells. Phenotypic analyses demonstrate increased pigment production and expanded dendritic networks that support efficient pigmentation. Molecular characterization indicates that these effects are associated with coordinated activation of {beta}-catenin signaling and actin-dependent cytoskeletal remodeling. The physiological relevance of these findings was further examined in vivo. Topical application of staurosporine to normal guinea pig skin increased baseline pigmentation without detectable inflammation. In addition, staurosporine accelerated repigmentation in a rhododendrol-induced leukoderma model by restoring functionally mature melanocyte populations and enhancing nuclear localization of {beta}-catenin. Together, these results identify staurosporine as a non-canonical modulator of melanocyte maturation and highlight the coordinated regulation of pigment production and dendritic remodeling as a key process supporting pigmentation in acquired hypopigmentary conditions. SummaryO_LIStaurosporine promotes non-canonical maturation of human melanocytes at sub-cytotoxic concentrations. C_LIO_LITreatment enhances both melanogenesis and dendritic remodeling, supporting functional pigmentation. C_LIO_LIStaurosporine increases baseline skin pigmentation in vivo without inducing inflammation. C_LIO_LIRepigmentation is accelerated in a rhododendrol-induced leukoderma model through restoration of mature melanocyte populations. C_LIO_LIThese findings highlight coordinated regulation of pigment production and dendritic morphology as a potential strategy to promote pigmentation in acquired hypopigmentary conditions. C_LI SignificanceLoss of melanocyte dendricity and functional maturation is a shared feature of multiple acquired hypopigmentary disorders, including vitiligo and chemical-induced leukoderma. This study demonstrates that staurosporine promotes dendritic remodeling and pigmentation in normal human melanocytes and enhances repigmentation in vivo. By identifying a melanocyte-intrinsic, ultraviolet-independent maturation program, our findings provide a biological framework for strategies aimed at restoring functional melanocytes in depigmented skin.

The time of day of UV exposure impacts both erythema and cancer development. To investigate whether UV-relevant clock-controlled gene expression can be modulated pharmacologically, we treated human skin explants with a combination of a cryptochoursome inhibitor and REV-ERB antagonist and then examined changes in gene expression of a limited number of core clock and clock-regulated genes. mRNA levels of both the DNA repair factor XPA and cell cycle checkpoint kinase WEE1 were found to be significantly increased by treatment. This pilot study suggests that clock-controlled gene expression can be altered pharmacologically to possibly alter skin responses to UV radiation.

The aim of this study was to explore the scalp bacterial flora structure and functional characteristics in androgenetic alopecia (AGA) patients, analyze its association with disease phenotypes and unhealthy lifestyles, and provide a basis for clarifying AGAs microecological pathogenic mechanism and targeted interventions. A total of 7 AGA patients and 6 healthy controls (HC) were enrolled, with scalp microbial samples collected. High-throughput sequencing of the 16S rRNA V3-V4 region was used to analyze flora alpha/beta diversity, species composition and differential species. LEfSe and KEGG functional prediction screened marker bacteria and differential pathways, and clinical/lifestyle data were collected for inter-group comparisons. No significant difference in Chao index was observed between groups (P>0.05), but Shannon/Simpson indices/Pielou evenness (P<0.01) and intra-group Bray-Curtis distance (P<0.001) were significantly higher in the AGA group, indicating reduced community stability. Staphylococcus dominated healthy scalps; the AGA group had fewer symbiotic bacteria but enriched Acinetobacter, Pseudomonas, andCutibacterium. LEfSe identified Firmicutes/Staphylococcus as HC markers and Proteobacteria/Gammaproteobacteria/Acinetobacter/Pseudomonas as AGA dysbiotic flora. KEGG showed upregulated metabolic, immune and cell motility pathways in AGA (P<0.05), with only infectious diseases pathway enriched in HC. AGA patients had more frequent hair washing and higher rates of staying up late, high-fat diet and insufficient fruits/vegetables (all P<0.05). In conclusion, AGA patients have typical scalp microecological dysbiosis closely related to unhealthy lifestyles, which may accelerate alopecia by inducing follicular inflammation. Scalp flora can be potential biomarkers and targets for AGA assessment and intervention.

Cutaneous squamous cell carcinoma (cSCC) represents a growing public health burden, with incidence projected to increase 23-29% over the coming decade. Topical immunoprevention strategies targeting the PD-L1/PD-1 and TLR4 axes have demonstrated preclinical efficacy, yet optimal intervention timing in humans remains undefined. To address this gap, single-cell RNA sequencing was performed on matched sun-protected (SP), sun-damaged (SD), and actinic keratosis (AK) biopsies from the same individuals, along with independent cSCC cases. Immune checkpoint and innate inflammatory signals were detectable as early as SD skin, prior to histologically confirmed dysplasia. Monotonically increasing expression of CD274 (PD-L1), CTLA4, PDCD1, CD27, and STAT1, alongside progressive TLR4-MYD88 innate immune signaling, was revealed through pseudobulk data analysis, with earliest upregulation at the SD stage. Fuzzy c-means trajectory clustering identified cell-typespecific programs across dendritic cells, macrophages, T cells, fibroblasts, endothelial cells, and keratinocytes. Dendritic cells shifted from early inflammatory antigen-presenting programs toward late PD-L1/IFN-regulatory states; macrophages showed monotonically increasing TLR4-associated myeloid activation; and T cells defined a "hot but exhausted" microenvironment in established cSCC. These findings identify SD and AK as biologically active stages for topical immunoprevention and provide a cellular roadmap for PD-L1/PD-1 and TLR4 blockade strategies.

BackgroundNon-segmental vitiligo(NSV) shows marked heterogeneity in activity, progression, and treatment response. Reliable clinical markers that predict prognosis and patient-reported outcomes are lacking. ObjectivesTo identify clinicodemographic and clinical predictors of disease extent, progression, repigmentation, treatment dependency, noticeability, and psychosocial impact in NSV. MethodsIn this prospective cohort study, 275 patients with NSV were followed for 12 months. Sixteen baseline variables, including demographic features, autoimmune history, and clinical markers (koebnerization, confetti and trichrome patterns, leukotrichia, mucosal, acral, and periorificial involvement), were recorded. Outcomes included body surface area(BSA), progression, repigmentation, treatment dependency, Vitiligo Noticeability Scale(VNS), and quality-of-life indices(VIS-22, DLQI, C-DLQI, F-VIS). Multivariable analyses and cluster analysis were performed at 6 and 12 months. ResultsMarkers of disease activity leukotrichia, trichrome and confetti lesions, koebnerization, and mucosal, acral, and periorificial involvement were strongly associated with greater BSA, poor repigmentation, higher noticeability, and treatment dependency. Leukotrichia was consistent predictor of poor repigmentation and high VNS. Family history of autoimmunity predicted progression and treatment dependency. Early-onset vitiligo showed lower disease extent but greater family-related psychosocial burden. Cluster analysis identified severe, intermediate, and mild phenotypes with distinct therapeutic responses. ConclusionsSimple clinical markers can stratify NSV patients into prognostic subgroups, enabling individualized treatment and counseling. Plain Language SummaryVitiligo behave variably in different people, some people may have slow-spreading course, while others develop widespread or persistent patches. In this study, we followed 275 people with non-segmental vitiligo for one year to find signs on the skin that could predict how the disease would behave and how it would affect daily life. We found that features such as white hair within patches (leukotrichia), speckled (confetti) or three-colored lesions (trichrome), new patches appearing after injury (koebnerization), and involvement of the lips, mouth, hands, feet were linked to more severe disease, poorer response to treatment, and greater cosmetic concern. A family history of autoimmune disease increased the risk of worsening vitiligo. Patients who developed vitiligo early in life had less skin involvement but greater emotional and family-related impact. These easily recognized signs can help doctors and patients plan treatment and set realistic expectations. Significance of the studyNon-segmental vitiligo (NSV) has a heterogeneous and unpredictable clinical course with variable progression and response to therapy. However, robust prospective data linking these markers with long-term outcomes and patient-reported measures remain limited. In our prospective cohort of 275 patients, clinical markers such as leukotrichia, trichrome and confetti lesions, koebnerization, and acral/mucosal/periorificial involvement, were strongly associated with greater disease extent, poorer repigmentation, higher treatment dependency, and increased noticeability. Leukotrichia consistently predicted poor repigmentation. Thereby, prognostic stratification can also improve patient counselling regarding expected repigmentation, treatment duration, and psychosocial burden.

Abstract: Background: More than half of metastatic melanomas arise from patients initially diagnosed with early-stage melanoma. Objective biomarkers are needed to better identify high-risk patients. Objective: To evaluate the prognostic value of multiple histopathological characteristics in predicting distant metastasis risk, in early-stage melanoma. Methods: Using data from discovery set (n=442) and a population-based validation cohort (n=306, sampled from 5,815 patients) of the Dutch Early-Stage Melanoma (D-ESMEL) study, we investigated 14 histopathological characteristics of melanoma and their tumor micro-environment (TME) in an unprecedented integration, by expert pathologist scoring and automated quantitative measurements derived from a validated automated segmentation. Results: Increased immune infiltrates (40% in cases vs. 50% in controls) were associated with lower risk of metastasis. Automated immune cell density was predictive in both the discovery set and the validation cohort, outperforming the manual pathological tumor infiltrating lymphocytes. The remaining histopathological features, including mitotic activity, did not retain independent value after controlling for current staging variables. Limitations: TME evaluation in standard Hematoxylin-Eosin slides. Conclusion: TME reaction is an important determinant of melanoma progression. The automated quantification of immune cell density appears to be a biomarker for distant metastasis risk. Further investigation into specific immune cell subtypes is required to facilitate clinical integration.

Hidradenitis suppurativa (HS) is a chronic, debilitating, inflammatory skin disorder. Medications have been reported in association with cases of new-onset HS or exacerbation of existing disease; however, the extent of this risk is unclear. We queried the FDA adverse event reporting system (FAERS) from 2003-2023 to identify drug-specific reporting signals for HS. We stratified reports by whether HS was listed as an indication (Drug-Worsened, DW) or not (Drug-Induced, DI) to distinguish disease flares from de novo disease. Primary suspect drugs with > 3 HS reports were included. Disproportionality was quantified using reporting odds ratio (ROR) with Wald 95% confidence intervals (CI). Time-to-onset was also evaluated. We identified 5,529 HS reports: 3,725 DW and 1,804 DI. Females comprised 63% (mean age 41) and the US was the top reporting country (81.8% DW; 53.66% DI). In the DI group, statistically significant signals were observed for immunomodulators also used to treat HS including adalimumab (n=506, ROR= 12.6 [11.3-14.0]) infliximab (n=108, ROR=8.2 [6.7-10.0]), and secukinumab (n=79, ROR=6.6 [5.2-8.2]), consistent with paradoxical reactions. Median time-to-onset was 22 days for secukinumab, compared to 312 and 319 days for adalimumab and infliximab. Signals were also identified for isotretinoin (n=28, ROR= 6.2 [4.2-8.9]), and for antineoplastic agents including cytarabine (n=25, ROR= 24.7 [16.6-36.6]) and omacetaxine (n=8; ROR= 7416 [CI 2923-18816]), which may reflect reported eccrine hidradenitis. In the DW group, adalimumab (n=2967), secukinumab (n=67), and infliximab (n=57) predominated but displayed lower RORs (0.72-1.4), likely reflecting indication bias. While mechanisms of drug-associated HS require further clarification, our findings demonstrate significant associations and highlight the importance of dermatologic monitoring when initiating certain agents.

Hailey-Hailey disease (HHD) is a genetic skin blistering disorder lacking approved treatments despite linkage to ATP2C1 variants 25 years ago. Since knockout mice did not replicate HHD, we ablated ATP2C1 in human keratinocytes or chemically inhibited its encoded Golgi calcium pump SPCA1. In organotypic epidermis, SPCA1 deficiency or inhibition reproduced HHD pathology, disrupting desmosomal cadherins and severing cell-cell junctions, termed acantholysis. RNA sequencing of heterozygous cells identified dysregulation of actin and Rho GTPases along with EGF receptor signaling as potential pathogenic drivers. Accordingly, SPCA1-depleted organotypic epidermis and HHD biopsies exhibited cortical actin disorganization and hyper-phosphorylation of the Rho kinase (ROCK) target, myosin light chain. Rho activation was sufficient to induce acantholysis, while ROCK inhibition partially restored heterozygous keratinocyte cohesion. A fluorescent biosensor demonstrated ERK hyper-activation in heterozygous cells along with desmosomal cadherin mis-localization. Importantly, treating SPCA1-deficient keratinocyte sheets with MEK and ROCK inhibitors together fully restored their integrity. Our results show HHD blistering is driven by desmosome and cortical actin dysfunction that was mitigated by targeting MEK and ROCK with repurposed drugs, offering a viable treatment strategy. Moreover, our model provides a blueprint for replicating genetic epidermal disorders to delineate pathogenic mechanisms and vet therapeutics for other orphan skin diseases. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/726679v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@b2de6aorg.highwire.dtl.DTLVardef@128411borg.highwire.dtl.DTLVardef@1ca760forg.highwire.dtl.DTLVardef@10cd6c7_HPS_FORMAT_FIGEXP M_FIG C_FIG

Atopic dermatitis (AD) is a highly prevalent, relapse-remitting, inflammatory skin disease, the hallmark symptom of which is chronic itch. Mechanisms underlying AD itch are multifactorial, involving various cells, receptors, and mediators. Developing a physiologically relevant, human model system for AD itch research and drug development is crucial. To this end, human induced pluripotent stem cell-derived sensory neurons (iPSCSNs) were cultured with human primary keratinocytes to form deconstructed skin models. Using Ca2+-imaging in a direct contact, 2.5D co-culturing format, which mimics natural skin innervation and permits both paracrine exchange and juxtacrine signaling, iPSCSNs exhibited functional TRPA1 responses not seen in monotypic iPSCSN cultures or in iPSCSNs conditioned with keratinocyte medium. Different AD-associated cytokines were used to stimulate the co-culture systems to mimic an inflamed lesional skin environment, whereby TNF was found to increase iPSCSN chemosensitivity. Finally, both TRPA1 and JAK1/2 inhibition reduced iPSCSN responses to pruritogens (TSLP, IL-31), thus supporting TRPA1 as a therapeutic target for AD itch in humans. This study demonstrates that human deconstructed skin models can be a useful tool in AD and broader pruritus research. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/724000v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@11c0c9borg.highwire.dtl.DTLVardef@7fa518org.highwire.dtl.DTLVardef@2fe7a2org.highwire.dtl.DTLVardef@1105fa7_HPS_FORMAT_FIGEXP M_FIG C_FIG

Background Lichen Planus (LP) is a chronic inflammatory disorder that can affect the skin, hair, nails, and mucous membranes. Oral lichen planus (OLP), the most common LP subtype, is a disease of the oral mucosa, often diagnosed through clinical examination and histopathological confirmation. Extracellular vesicles (EVs) transfer proteins, lipids, and nucleic acids among cells and have become increasingly studied for their potential as minimally invasive diagnostic biomarkers and therapeutic agents in inflammatory and autoimmune diseases. Methods PUBMED and Embase were searched from inception through June 27th, 2026. Human studies investigating EV-associated miRNA or protein biomarkers in LP and its subtypes were included, with risk of bias assessed using a modified Newcastle-Ottawa Scale. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) and BRMA models when sufficient data were available. Results Ten articles met the inclusion criteria, encompassing biomarker discovery, functional, and mechanistic studies of EVs in OLP. These included studies (n = 10) comprised 298 individuals with LP (weighted mean age 50.7 years; 61.5% female) and 194 controls (weighted mean age 47.8 years; 58.5% female). OLP-specific cohorts (n = 9 studies) included 261 individuals with OLP (weighted mean age 50.7 years; 61.4% female). Although no individual EV-associated miRNAs or proteins overlapped across studies, EV-associated miRNAs demonstrated substantial heterogeneity, while EV-associated protein findings centered on pathways related to antigen presentation, inflammatory signaling, and immune activation. Several candidate biomarkers, including miR-4484, miR-34a-5p, GJA1, PDIA3, and Cx43, showed potential diagnostic or prognostic relevance. ROC analyses demonstrated good diagnostic utility for miR-4484 (AUC = 0.81), and the combination of GJA1 and Cx43 showed the strongest discriminatory ability (AUC = 0.892). The diagnostic accuracy meta-analysis showed good discrimination (pooled AUC = 0.89). Functional and mechanistic studies suggested that EVs may actively contribute to OLP pathogenesis through promoting epithelial injury and activating inflammatory signalling pathways. Conclusions EV-associated miRNAs and proteins are potential biomarker candidates for LP and may provide insight into the inflammatory and immune mechanisms underlying disease pathophysiology. Functional and mechanistic evidence further suggests that EVs may play an active role in disease progression. However, current evidence has limitations such as small sample sizes and methodological heterogeneity. Larger, standardized, and longitudinal studies are needed to v

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer associated with substantial morbidity and mortality in advanced stages. Despite its well-described stepwise progression from actinic keratosis to invasive disease, robust molecular markers for stage discrimination and clinical decision-making remain limited. We sought to define the transcriptional continuum underlying cSCC progression, identify stage-associated biomarkers, and assess the broader relevance of these programs across human malignancies. Bulk RNA sequencing (HTG EdgeSeq) and spatial transcriptomics (GeoMx) were performed on biopsies from eight patients, each presenting multiple disease stages (healthy skin, premalignant lesion, tumor core, and invasive front) within the same lesion field, enabling within-patient analysis of progression. Spatial transcriptomic analyses identified more than 2,000 differentially expressed genes whose expression varied across disease stages. These genes were organized into 18 coordinated expression programs reflecting progressive biological rewiring during tumor evolution. Proliferation, extracellular matrix remodeling, inflammation, and stress-response pathways were progressively upregulated, whereas epithelial differentiation and metabolic processes, including lipid and amino acid metabolism, were downregulated. Macrophages exhibited distinct metabolic reprogramming, with increased purine metabolism, glycolysis, and pyruvate metabolism across progression. To evaluate the broader clinical relevance of these progression-associated programs, we developed a reproducible Snakemake pipeline to systematically screen 32 solid and hematologic malignancies from The Cancer Genome Atlas (TCGA). A combined cSCC-progression signature was significantly associated with poor overall survival (P < 0.05) in 10 additional cancer types. Finally, we identified 12 stage-informative biomarkers, whose spatially restricted expression patterns were validated using Visium HD. This study provides a spatially resolved and stage-aware transcriptomic map of cSCC progression, identifies coordinated gene programs underlying disease evolution, and defines progression-associated signatures with prognostic relevance across multiple cancers, highlighting their potential translational value.

How the cutaneous microenvironment influences early melanomagenesis is poorly understood. Here, we assessed the effects of three immune perturbations on premalignant melanocyte expansion in an autochthonous mouse model of disease. Depletion of regulatory T (Treg) cells markedly accelerated melanoproliferation, an unexpected phenotype that was associated with monocyte and macrophage infiltration, the production of inflammatory and angiogenic factors, and vascular leakage. In line with these observations, single cell transcriptomic analysis of Treg cell deficient skin revealed robust accumulation of monocyte-derived macrophages with tissue remodeling characteristics. Acute UV irradiation and 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity had analogous effects on both the cellular microenvironment of the skin and the expansion of local premalignant melanocytes. Treatment with the anti-inflammatory agent dexamethasone attenuated DNFB-induced melanocyte expansion and vascular remodeling. Collectively, these results identify a conserved inflammatory axis linked to the early outgrowth of oncogenic melanocytes in the skin.

BACKGROUND Erythema nodosum leprosum (ENL) is a severe inflammatory complication of leprosy associated with disability, morbidity and mortality. Impairment of health-related quality of life (HRQoL) in ENL has been reported using the Dermatology Life Quality Index (DLQI) and the 36-Item Short Form Health Survey (SF-36), the latter validated in people affected by leprosy. Understanding the correlation between these measures is important to determine whether the shorter dermatology-specific DLQI provides a valid and practical measure of HRQoL in ENL. OBJECTIVES To examine the relationship between DLQI and SF-36 scores in individuals with ENL using data from the Methotrexate and Prednisolone study in ENL (MaPs in ENL). METHODS A post-hoc analysis of prospectively collected HRQoL data from the trial sites in India, Indonesia, and Nepal of the MaPs in ENL multicentre randomised clinical trial was performed. HRQoL was assessed using the DLQI and SF-36 at enrolment and at weeks 24, 48 and 60. Associations between DLQI and SF-36 physical (PCS) and mental (MCS) component summary scores were evaluated using correlation analyses and multivariable linear regression at enrolment, and linear mixed-effects models during follow-up adjusted for age, sex, recruiting centre and enrolment SF-36 scores. RESULTS A total of 383 paired HRQoL assessments from 129 participants were analysed. At enrolment, HRQoL impairment was substantial (median DLQI 19, IQR 15-21; mean PCS 30.3 + - 7.3; mean MCS 33.3 + - 8.4). DLQI scores improved markedly during follow-up. Across all timepoints, DLQI was strongly inversely correlated with PCS and MCS (both p<0.001). In adjusted analyses, higher DLQI scores were consistently associated with lower PCS and MCS. At enrolment, each 1-point increase in DLQI was associated with a 0.66-point reduction in PCS and a 0.51-point reduction in MCS (both p<0.001). These associations remained strong during follow-up, with no evidence that they varied over time. CONCLUSIONS DLQI scores were strongly and consistently associated with SF-36 physical and mental health scores. These findings support the use of the DLQI as a practical patient reported outcome measure to assess the HRQoL associated with ENL and its change following treatment.

Deficiency of the Interleukin-36 Receptor antagonist (DITRA) is a rare autoinflammatory condition which commonly manifests as severe, recurrent episodes of Generalized Pustular Psoriasis (GPP). Loss-of-function mutations in the IL36RN gene result in unopposed IL-36 cytokine signalling leading to severe psoriatic inflammation, which can be successfully treated with Anti-IL-36 receptor (IL-36R) monoclonal antibodies. Despite such advances, there remain some key questions concerning how loss of a functional IL-36R antagonist predisposes to GPP, including identifying the potential impacts of IL36RN mutations on skin homeostasis. To address this question, we investigated the consequences of IL-36Ra deficiency using Il36rn-/- mice, which recapitulate the severe psoriatic inflammation observed in DITRA patients. Here, we demonstrate, that in overtly healthy Il36rn-/- mice, prior to disease onset, there is disrupted dermal immune homeostasis, characterised by decreased expression of the chemokine CCL27. Altered skin homeostasis occurred in association with dysbiosis of the skin microbiome, characterised by a significant outgrowth of the commensal bacteria, Cutibacterium acnes. Importantly, intradermal administration of recombinant CCL27, prior to disease induction, significantly reduced the enhanced severity of psoriasiform inflammation, demonstrating a central role for this chemokine in regulating predisposition to increased severity. Transcriptomic analysis of GPP patients skin also revealed decreased CCL27 expression in non-lesional, as well as lesional, compared to healthy skin, indicating that this chemokine may also play a key instructive role among DITRA patients. Together, these data identify a novel mechanism through which IL-36Ra deficiency alters dermal homeostasis and predisposes to increased severity of psoriatic disease observed in DITRA patients.

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune dysregulation. Emerging clinical and experimental evidence suggests that endogenous lipid (endolipid) signaling systems, including the endocannabinoid system (ECS), represent a promising therapeutic target to treat psoriasis; however, comprehensive characterization of small-molecule endolipids and related proteins in psoriatic skin and their relationship to systemic changes remains limited. Here, we used the imiquimod (IMQ)-induced mouse model of psoriasis to perform combined lipidomic and transcriptional profiling of endolipid signaling in both skin and plasma. Targeted lipidomics revealed a striking divergence between tissues: most endolipids increased in inflamed skin but decreased in plasma, including the canonical ECS lipids anandamide and 2-arachidonoylglycerol. In contrast, selected lipid species, including taurine-conjugated metabolites (both N-acyl taurines and bile acids), were elevated in both tissues, indicating pathway-specific regulation. Targeted transcriptional analysis of whole skin showed reduced expression of key endolipid biosynthetic enzymes (Napepld, Dagla, Daglb) and the cannabinoid receptor Cnr1, while Cnr2 and ECS-related metabolic enzymes remained unchanged. Additional alterations were observed in transcripts involved in related endolipid signaling (Trpv1, Trpv4, Ppara, Pparg, Gpr55), bile acid metabolism (Fxr, Bsep, Fabp4, Fabp5, Cyp27a1, Cyp8b1), and inflammatory pathways (Cox-2). To resolve this apparent discrepancy between lipid levels and gene expression, we performed compartment-specific analyses of epidermal and dermal layers. These revealed a predominantly suppressive epidermal response across multiple ECS-related proteins, contrasted by a more variable dermal profile with selective preservation or upregulation, particularly of Cnr2. Together, these findings demonstrate that psoriasiform inflammation is associated with compartment-specific remodeling of endolipid signaling across skin and systemic compartments, underscoring the functional heterogeneity of epidermal and dermal layers. This dataset provides novel insights into the dysregulation of endolipid signaling systems in psoriasis and provides a foundation for the development of spatially informed, lipid-based therapeutic strategies.

Keloids are fibroproliferative skin disorders arising following dermal injury that extend beyond the original wound margins. Their pathogenesis remains poorly understood, and current treatments are associated with high recurrence rates. Identifying transcriptomic biomarkers that distinguish keloids from other skin and scar phenotypes may provide insight into disease mechanisms and facilitate the development of targeted therapeutic approaches. However, previous transcriptomic studies have often been limited by small sample sizes, pairwise comparisons between tissue classes, heterogeneous data-integration strategies, and a reliance on conventional differential gene expression (DGE) analysis. Here, we employed a multi-stage machine learning (ML) workflow for robust keloid biomarker discovery using transcriptomic datasets derived from both bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq). We assembled and harmonized, to the best of our knowledge, the largest curated cross-study keloid transcriptomic cohort currently available, comprising 81 samples from 13 independent studies spanning four clinically relevant tissue classes: normal skin, normotrophic scar, hypertrophic scar, and keloid scar. Through study-aware cross-validation, feature selection, partition-stability analysis, and bootstrap validation across multiple ML classifiers, we identified a panel of eight highly consistent biomarkers capable of distinguishing keloid from non-keloid samples. These biomarkers were associated with dysregulation of extracellular matrix homeostasis, fibrosis-resolution pathways, vascular remodelling, and metabolic reprogramming. Comparison with conventional DGE analysis demonstrated substantial agreement while also highlighting important differences between the two approaches. In particular, FASN was consistently identified by the ML workflow as an upregulated discriminatory biomarker despite exhibiting weak, non-significant differential expression in the DGE analysis. Cell-type-specific analysis further supported this finding, revealing significant FASN upregulation in fibroblast and vascular endothelial populations. These results demonstrate that ML and DGE capture complementary aspects of transcriptomic variation. This study provides a robust strategy for cross-study transcriptomic biomarker discovery and identifies candidate genes and pathways for future mechanistic and therapeutic investigation in keloids. 1 Author SummaryKeloids are abnormal scars that continue to grow beyond the original wound and can be difficult to treat because they frequently recur after therapy. Although many studies have investigated the biology of keloids, the molecular mechanisms that distinguish them from other scar types remain incompletely understood. Identifying biomarkers involved in keloid formation may help inform improved treatment strategies. Previous transcriptomic studies have often been limited by small sample sizes and inconsistent analytical approaches. In this study, we combined gene-expression data from multiple independent studies to create, to the best of our knowledge, the largest cross-study transcriptomic collection available for keloid analysis. We then applied several machine learning approaches to identify genes that consistently distinguished keloids from other skin and scar phenotypes. The identified biomarkers were associated with extracellular matrix remodeling, fibrosis, vascular function, and cellular metabolism. One gene involved in fatty-acid synthesis, FASN, was repeatedly identified by the machine learning analyses despite being overlooked by conventional gene-expression methods. Additional single-cell analyses confirmed elevated FASN expression in specific cell populations within keloid tissue. More broadly, this work provides a strategy for discovering robust biomarkers from heterogeneous biological datasets and identifies molecular targets for future studies of keloid disease.

Cooling the skin may increase its tolerance to mechanical loading and decrease the risk of developing pressure ulcers. Yet, the mechanisms of action (e.g. cooling-modulation of cytotoxic, post-occlusive hyperaemia), and their individual variability, remain unclear. We investigated the effects of different cooling levels (24{degrees}C and 16{degrees}C) on microvascular, inflammatory and perceptual responses to mechanical loading of the sacrum in healthy young (N=23) and older adults (N=19), and in spinal cord injury patients (SCI; N=10). Healthy participants underwent 45-min loading (~60 mmHg) and 20-min unloading of the sacrum, using an instrumented indenter probe set at either 38{degrees}C (control condition), 24{degrees}C or 16{degrees}C. SCI participants completed a more conservative protocol (i.e. 25min, ~45mmHg loading, 38{degrees}C and 16{degrees}C conditions). Pre-insult skin structure was characterised with optical coherence tomography; skin blood flow (SkBF) at the loading site was continuously measured, alongside thermal acceptability; and post-insult inflammatory responses were determined via skin-sebum cytokines analyses. Compared to control, 24{degrees}C- and 16{degrees}C-cooling induced a similar ~8-fold decrease in peak post-occlusive reactive hyperaemia in healthy participants, with similar temperature-related differences observed in SCI. Pro-inflammatory cytokines decreased post-insult; yet this occurred similarly across all temperatures and groups. The majority of participants ([&ge;]70%) rated both 24{degrees}C- and 16{degrees}C-cooling as thermally acceptable. We conclude that cooling is a potent modulator of the skin microvascular response to mechanical loading in younger, older, and vulnerable skin (SCI). These findings can inform design parameters for thermal technology aimed at preventing the loss of skin integrity (e.g. integrating 24{degrees}C-cooling in support surfaces and skin wearables).

Accurate risk stratification of pigmented skin lesions is critical for early melanoma detection and for reducing unnecessary excisions. Artificial intelligence (AI) is increasingly applied to dermoscopic image analysis, but its diagnostic performance relative to standard dermoscopy in real-world clinical settings remains uncertain. To address this gap, we conducted a systematic review and meta-analysis of prospective clinical studies directly comparing AI alone, dermoscopy, and AI-assisted clinicians for malignancy risk assessment of pigmented skin lesions. We systematically searched PubMed, Embase, Web of Science, and Cochrane Library from inception to January 2026. Ten studies with 17 diagnostic arms (10 dermoscopy arms, 6 AI-alone arms, and 1 AI-assisted clinician arm) were included. Pooled sensitivity and specificity were 0.773 (95% CI, 0.648-0.863) and 0.793 (95% CI, 0.673-0.877) for dermoscopy, and 0.757 (95% CI, 0.428-0.928) and 0.859 (95% CI, 0.619-0.958) for standalone AI. Summary ROC curves showed overlapping performance, indicating that autonomous AI is broadly comparable to dermoscopy but does not demonstrate a consistent advantage. Heterogeneity in AI performance was driven almost entirely by threshold effects rather than by differences in inherent model capacity. AI-assisted clinicians showed promising results (sensitivity 1.000, specificity 0.837) in a single study, but more evidence is needed. Our findings suggest that, at present, AI should be viewed as a complementary decision-support tool rather than a replacement for dermoscopic evaluation. The study provides valuable evidence for clinicians, guideline developers, and researchers working on AI integration into melanoma diagnostic pathways.

Fibroproliferative diseases such as systemic sclerosis are complex conditions characterized by chronic skin inflammation and progressive fibrosis, with fibroblast activation as a central feature. While Transforming Growth Factor Beta (TGF-{beta}) signaling is a well-established driver of fibrosis in SSc, inflammatory pathways such as Nuclear Factor Kappa B (NF-{kappa}B) also contribute substantially to disease morbidity. We previously identified CD109 as a TGF-{beta} co-receptor and negative regulator of fibrotic signaling; however, its role in inflammatory signaling remains unknown. Here, we investigate the function of CD109 in regulating inflammatory signaling in skin fibroblasts. We show that, CD109 co-localizes and associates with Toll-like receptors (TLR2, TLR4) and tumor necrosis factor receptors (TNFRI, TNFRII), and that loss of CD109 enhances TNF--induced NF-{kappa}B activation and reprograms cytokine production in human dermal fibroblasts. Furthermore, both global and fibroblast-specific CD109 knockout mice exhibit increased immune cell infiltration and skin inflammation. In parallel, single-cell transcriptomic analyses across a pan-disease fibroblast atlas show that CD109 expression is preferentially maintained in structural and homeostatic fibroblast subtypes, whereas immune-interacting fibroblast subsets consistently display decreased CD109 levels. Pathway-level analyses of fibroblast pseudobulk samples reveal altered activity of canonical inflammatory pathways in SSc compared to healthy skin. Together, these findings identify CD109 as a fibroblast-intrinsic negative regulator of inflammatory signaling and suggest a broader role for CD109 in modulating inflammatory responses in systemic sclerosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/736423v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@be9e08org.highwire.dtl.DTLVardef@794173org.highwire.dtl.DTLVardef@b81eb5org.highwire.dtl.DTLVardef@1e811f5_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract: CD109 Restrains Fibroblast-Driven Inflammation by Modulating NF-{kappa}B Signaling. Generated using FigureLabs.ai and edited using Adobe Photoshop. C_FIG

Merkel cell carcinoma (MCC) is a neuroendocrine skin tumor that is frequently driven by integration of Merkel cell polyomavirus (MCPyV). In MCC, the MCPyV genome is truncated, but expression of the viral tumor antigens, truncated large tumor antigen (LTT) and small tumor antigen (sT), is maintained and drives uncontrolled proliferation. We introduced constitutive expression of the MCPyV T antigens (TAs) into primary mouse dermal fibroblasts (MDFs) to determine whether these cells are susceptible to MCPyV-driven transformation. TA expression alone in MDFs induced key MCC markers, cytokeratin-20 (CK20) and Sry-box transcription factor 2 (SOX2), and promoted anchorage-independent growth indicative of cellular transformation. Subcutaneous implantation of TA-transformed fibroblasts produced high-grade MCC-like tumors that grew persistently in immunodeficient NSG mice but not in immunocompetent C57BL/6 mice. Serial in vivo passaging of the tumor cell line enhanced tumor growth, reduced expression of p53-target genes and MHC-1, and was accompanied by a shift in T antigen isoform expression, with decreased LTT and increased sT expression. Our data demonstrate that MCPyV-driven tumors acquire immune-evasive adaptions during tumor progression in vivo and suggest that the anti-tumor immune response exerts selective pressure in MCC that favors expression of sT rather than LTT. The model established in this study provides a unique platform for studying evolution of MCPyV-driven tumors under immune pressure and identifying mechanisms of immune evasion in MCC that could be used to develop new therapeutic strategies. Significance StatementMCPyV tumor antigen expression transforms mouse dermal fibroblasts to generate MCC-like tumors. Serial in vivo passaging reveals tumor evolution under immune pressure, providing a model to study immune evasion mechanisms in MCC.