The extracellular matrix (ECM) is increasingly recognised as a dynamic regulator of tissue function beyond its traditional structural role. In the skin, the ECM supports tissue integrity while also controlling processes...The extracellular matrix (ECM) is increasingly recognised as a dynamic regulator of tissue function beyond its traditional structural role. In the skin, the ECM supports tissue integrity while also controlling processes such as stem cell maintenance, wound healing and disease progression. This review focuses on laminin-332, a key component of the epidermal-dermal junction. Its essential role in maintaining epidermal cohesion is illustrated by junctional epidermolysis bullosa, a severe inherited blistering disorder and recent advances in laminin-332-targeted genetic therapies are discussed. Beyond structural support, laminin-332 also mediates signalling through integrins and syndecans, thereby influencing epidermal homeostasis, migration, repair and the development of cutaneous squamous cell carcinoma. Its role in epidermal stem cell maintenance further links laminin-332 to skin ageing. The review also examines its functions in hair follicle biology, melanocyte behaviour, skin immunity and emerging evidence implicating laminin-332 in epidermal metabolism-an exciting area for future investigation. Finally, the structure and functions of other cutaneous laminins are compared with laminin-332 to help explain its specialised roles.
Skin cutaneous melanoma (SKCM) continues to pose significant therapeutic challenges owing to its aggressive nature and evolving resistance mechanisms. This study investigates the under-characterized role of Hippo pathway...Skin cutaneous melanoma (SKCM) continues to pose significant therapeutic challenges owing to its aggressive nature and evolving resistance mechanisms. This study investigates the under-characterized role of Hippo pathway effector TEAD4 in SKCM pathogenesis through integrated multiomics analysis of clinical cohorts (TCGA, GEO, immunotherapy cohorts) combined with functional validation in A375 cell models and xenograft systems. Our pan-cancer analysis identified TEAD4 overexpression as a strong prognostic indicator associated with poor survival and a potential association with inferior immunotherapy response. Functional experiments in A375 cells and xenograft models showed that TEAD4 knockdown impaired proliferation, migration and tumour growth while increasing necroptosis-related markers. Mechanistic investigation showed that TEAD4 directly binds the COL1A2 promoter and promotes its transcription. In A375 cells, COL1A2 overexpression attenuated TEAD4 knockdown-induced changes in AKT/mTOR signalling, necroptosis-related markers and malignant phenotypes. These findings support a TEAD4 and COL1A2 regulatory model associated with SKCM progression, AKT/mTOR pathway activity and necroptosis-related phenotypes, and suggest TEAD4 as a prognostic factor and potential biomarker associated with immunotherapy outcome that requires further validation.
Zengarini C, Giacometti T, Merli Y
… +10 more, Griffa D, Rapparini L, Natale A, Fruci M, Castellani G, Remondini D, La Placa M, Pileri A, Starace M, Curti N
Exp Dermatol
· 2026 Jun · PMID 42249670
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Wound edge assessment is a key component of chronic wound evaluation, but it remains highly subjective and affected by inter-observer variability, particularly when performed on two-dimensional clinical photographs. We r...Wound edge assessment is a key component of chronic wound evaluation, but it remains highly subjective and affected by inter-observer variability, particularly when performed on two-dimensional clinical photographs. We retrospectively analysed 1 860 wound images acquired during routine clinical practice and independently annotated by four expert clinicians. An automated image-analysis pipeline was used to segment the wound, standardise the peri-wound border region, and estimate the three-dimensional profile of the wound edge. We first tested whether geometry-derived edge profiles alone could reproduce clinical wound edge categories. We then evaluated whether adding global visual descriptors of wound shape, colour appearance, and surface pattern improved agreement with clinicians. Inter-clinician agreement was low, confirming the intrinsic subjectivity of wound edge classification. Geometry-based analysis identified coherent edge-profile patterns but showed poor correspondence with clinical annotations. In contrast, a supervised classifier incorporating both geometric and visual features achieved agreement comparable to, and in some comparisons higher than, the agreement observed among clinicians. Clinical wound edge assessment is not driven by edge geometry alone. Visual cues such as wound shape, colour appearance, and surface pattern appear to influence expert classification and may contribute to variability. Automated image-based analysis may support more reproducible wound edge assessment, provided that it is externally validated in diverse clinical settings.
The relapse of psoriasis precludes a complete cure and can result in multisystem comorbidities, making relapse prevention a critical clinical challenge. Clinically, psoriasis tends to worsen or relapse in winter, but the...The relapse of psoriasis precludes a complete cure and can result in multisystem comorbidities, making relapse prevention a critical clinical challenge. Clinically, psoriasis tends to worsen or relapse in winter, but the underlying mechanisms remain unclear. In this study, we utilized an imiquimod (IMQ)-induced psoriasis-like mouse model to investigate the role of cold stress in the exacerbation of psoriasis during winter. Our data indicate that cold stress significantly aggravates IMQ-induced psoriatic lesions. While cold stress alone does not directly induce psoriasis, it can promote the development of psoriasis-like lesions in mice exposed to low doses of IMQ. Single-nucleus transcriptome analysis demonstrated that cold stress leads to the remodelling of macrophage phenotypes in psoriatic lesions, with a notable increase in ACSL1+ macrophages. These cells exhibit higher intracellular neutral lipid content and produce more IL-1β, which in turn stimulates γδT cells to secrete more IL-17A. The increase of ACSL1+ macrophages is associated with cold stress-induced lipid synthesis in dermal adipocytes. Notably, the number of ACSL1+ IL-1β + macrophages is significantly increased in the skin of psoriasis patients in winter. Therefore, targeting the formation of ACSL1+ macrophages may be a potential strategy to prevent the worsening of psoriasis in winter.
Psoriasis (PS) is linked to altered polyamine metabolism, which may drive chronic inflammation and abnormal keratinocyte proliferation. We integrated transcriptomics and single-cell RNA sequencing (scRNA-seq) to identify...Psoriasis (PS) is linked to altered polyamine metabolism, which may drive chronic inflammation and abnormal keratinocyte proliferation. We integrated transcriptomics and single-cell RNA sequencing (scRNA-seq) to identify polyamine metabolism-related genes (PMRGs) as biomarkers for PS and elucidate their mechanisms. Through the application of differential expression analysis, three machine learning algorithms, combined with receiver operating characteristic (ROC) analysis and expression quantification, biomarkers related to polyamine metabolism in PS were identified. Furthermore, the expression of these biomarkers was verified through western blotting. These biomarkers were subsequently incorporated into a diagnostic nomogram. Further investigations of these biomarkers included enrichment analysis and immune infiltration analysis. Additionally, scRNA-seq analysis was conducted to annotate the cell types in PS, providing insights into the cellular mechanisms underlying the progression of PS. In PS samples, biomarkers PSME2, PSMB5, PSMC4, PSMB10 and SMOX were significantly upregulated, achieving an area under the ROC curve (AUC) > 0.9 in GSE13355. Western blotting confirmed their upregulation, aligning with bioinformatics results. These biomarkers were closely associated with inflammation, cell proliferation, energy metabolism and signalling pathways. scRNA-seq identified 11 cell types, with mature dendritic cell (mDC) showing notable proportional differences between PS patients and controls, marking them as key cells. mDC exhibited distinct developmental trajectories with branching heterogeneity, featuring a reduction in early stages and an increase in later stages. Biomarker expression levels were higher in the later stages of mDC differentiation. The five PMRGs-PSME2, PSMB5, PSMC4, PSMB10 and SMOX-identified through comprehensive analyses, emerged as significant biomarkers for PS, providing promising diagnostic targets and mechanistic insights for the early detection and targeted treatment of PS.
Ultraviolet B (UVB) irradiation initiates cutaneous vitamin D-related photochemistry from 7-dehydrocholesterol (7-DHC), which is also the immediate precursor of cholesterol via 7-dehydrocholesterol reductase (DHCR7). Thu...Ultraviolet B (UVB) irradiation initiates cutaneous vitamin D-related photochemistry from 7-dehydrocholesterol (7-DHC), which is also the immediate precursor of cholesterol via 7-dehydrocholesterol reductase (DHCR7). Thus, DHCR7 occupies a branch-point position linking cholesterol biosynthesis and UVB-associated vitamin D-related metabolism. How keratinocytes regulate this metabolic relationship under UVB remains unclear. We examined whether OPN1SW is associated with DHCR7 protein abundance, conditioned medium 25-hydroxyvitamin D3 [25(OH)D3] (a vitamin D-related readout) and sterol-pool responses in UVB-exposed keratinocytes. A UVB dose that preserved > 80% cell viability, 10 mJ/cm, increased OPN1SW protein abundance and reduced DHCR7 protein abundance in human epidermal keratinocytes and HaCaT cells. These changes were accompanied by increased conditioned medium 25(OH)D3 and a reduced cellular sterol-pool readout. OPN1SW overexpression increased DHCR7 protein abundance under basal conditions. Under UVB exposure, OPN1SW overexpression attenuated UVB-associated DHCR7 reduction, attenuated the UVB-associated increase in conditioned medium 25(OH)D3 and partially preserved the sterol-pool readout. Conversely, OPN1SW knockdown exacerbated DHCR7 reduction under UVB and was accompanied by higher conditioned medium 25(OH)D3 and a lower sterol-pool readout. DHCR7 knockdown produced concordant shifts in these readouts, supporting a contributory role for DHCR7. Together, these findings support the presence of a UVB-responsive OPN1SW-DHCR7 module that may contribute to keratinocyte adaptation to UVB exposure.
This systematic review evaluates the clinical applications of reflectance confocal microscopy (RCM) in paediatric dermatology. The objective was to summarise evidence on the diagnostic and monitoring value of RCM in pati...This systematic review evaluates the clinical applications of reflectance confocal microscopy (RCM) in paediatric dermatology. The objective was to summarise evidence on the diagnostic and monitoring value of RCM in patients aged ≤ 18 years across dermatologic conditions. Eligible studies included original studies, observational studies, case series and case reports that used RCM in paediatric patients; non-original studies and those lacking extractable paediatric data were excluded. MEDLINE and Web of Science were searched on June 23, 2025. Risk of bias in observational studies was assessed using the modified published criteria. Data were synthesised narratively due to heterogeneity in study design, populations and outcomes. Seventy-three studies met the inclusion criteria which were classified across four condition groups: the 'Neoplastic and related lesions' category (25 studies), 'Congenital anomalies' (8), 'Inflammatory conditions' (30), and 'Infections and infestations' (14). Because some studies evaluated more than one condition, they were included in multiple categories; therefore, category-specific counts exceed the number of unique included studies. Across categories, RCM facilitated non-invasive diagnosis, differentiation of clinically similar conditions, and longitudinal monitoring, especially for melanocytic lesions, congenital pigmentary disorders, lichen sclerosus, vitiligo, acne, molluscum contagiosum, verruca plana, dermatophytosis and scabies. Several studies emphasised the advantages in sensitive regions, such as the genital area. Risk-of-bias assessment revealed variable methodological rigour, reflecting a predominance of observational designs and limited paediatric-specific data. Study heterogeneity, small sample sizes and frequent reliance on case reports or series limited evidence. Overall, findings support RCM as a safe, repeatable tool that reduces reliance on invasive procedures and aids diagnosis and treatment monitoring in paediatric dermatology. Trial Registration: PROSPERO CRD420251018599.
Water-filtered infrared-A (wIRA) has been proposed to enhance tissue perfusion and modulate fibrosis, but clinical evidence in morphea (localised scleroderma) is limited. We conducted a prospective, intra-individual pilo...Water-filtered infrared-A (wIRA) has been proposed to enhance tissue perfusion and modulate fibrosis, but clinical evidence in morphea (localised scleroderma) is limited. We conducted a prospective, intra-individual pilot split-study in 10 adults (six female; mean age 47.6 ± 19.0 years). One plaque per patient received wIRA using a Hydrosun device (30 min, three times weekly, for 20 weeks; 60 sessions); a clinically comparable contralateral plaque served as untreated control. Blinded assessments at baseline, after 30 and after 60 sessions comprised high-frequency ultrasound (22 MHz; primary endpoint), durometry, Patient Global Impression of Change and a Skin-Change-Perception scale; safety was recorded throughout. Outcome measurements showed substantial inter-individual variability, and irradiated plaques did not significantly improve compared with baseline or with untreated control plaques. However, treatment was well tolerated; two participants reported transient mild burning during early sessions, and no serious adverse events were observed. Larger, adequately powered trials with optimized irradiation parameters and complete follow-up are warranted to clarify the role of wIRA in morphea.
This review provides a comprehensive overview of macrophage heterogeneity, polarisation dynamics, metabolic reprogramming and multicellular interactions of macrophages in psoriasis. We discuss how single-cell technologie...This review provides a comprehensive overview of macrophage heterogeneity, polarisation dynamics, metabolic reprogramming and multicellular interactions of macrophages in psoriasis. We discuss how single-cell technologies have revealed diverse macrophage subsets and explore the metabolic profile of macrophages in psoriasis. Furthermore, we examine the central role of macrophages in intercellular networks with keratinocytes, T helper 17 (Th17) cells, neutrophils, fibroblasts and sensory neurons. Additionally, we summarise the novel signal way of macrophages and tissue injury by macrophages. Finally, we summarise emerging therapeutic strategies-including metabolic modulators, signalling pathway inhibitors, advanced delivery systems and cell-based therapies. By integrating recent insights from single-cell omics, spatial transcriptomics and metabolic studies, this review underscores the potential of macrophage-focused interventions for psoriasis treatment.
Psoriasis is a complex immune-mediated disease closely linked to multiple systemic comorbidities. Although Mendelian randomization (MR) studies have been widely applied to investigate its potential risk factors, existing...Psoriasis is a complex immune-mediated disease closely linked to multiple systemic comorbidities. Although Mendelian randomization (MR) studies have been widely applied to investigate its potential risk factors, existing evidence remains fragmented and sometimes contradictory, limiting clinical translation. This study aimed to systematically consolidate MR findings on psoriasis and to develop an interactive online platform to support clinical decision-making. We systematically searched PubMed, Embase, and Web of Science for psoriasis-related MR studies published up to December 31, 2025, and performed a structured organization and evidence synthesis of the eligible studies. We also developed the MR-PsO Atlas platform using R and Shiny, integrating evidence retrieval, comparative analysis, and exploratory meta-integration where basic comparability was met. A total of 346 MR articles were included, from which 1046 causal associations were extracted. Overall, the findings support an association between disrupted lipid metabolism-particularly elevated LDL-C and certain phospholipid species-and increased psoriasis risk. The results also suggest possible causal links between psoriasis and psychiatric conditions such as depression, and identify IFNLR1 and APOF as potential novel therapeutic targets. For controversial findings, including those related to blood lipids and cancer risk, we further evaluated directional consistency across studies through exploratory meta-integration and discussion of heterogeneity. In addition, the MR-PsO Atlas platform has been successfully deployed and is openly accessible for the retrieval, comparison, and visualization of causal evidence. This study systematically collated published MR evidence on psoriasis and constructed a corresponding evidence atlas to support the retrieval, comparison and interpretation of causal findings. The results highlight multidimensional pathogenic mechanisms ranging from metabolism to immunity. The MR-PsO Atlas platform provides a practical tool for integrating genetic evidence with clinical practice and may help advance precision prevention and management of psoriasis.
Skin homeostasis and self-renewal are partially maintained by interfollicular stem cells (ISCs), located in the basal layer above the dermal papillae of the dermo-epidermal junction (DEJ). Aging leads to a decline in ski...Skin homeostasis and self-renewal are partially maintained by interfollicular stem cells (ISCs), located in the basal layer above the dermal papillae of the dermo-epidermal junction (DEJ). Aging leads to a decline in skin renewal and a concurrent reduction in stem cell potential. It is also marked by disorganization of the extracellular matrix in both the DEJ and dermis, and flattening of the DEJ. To better understand ISCs aging, new methods are needed to characterize ISCs and their environment. Since mechanical properties of cells and their substrate influence cell fate, we employed atomic force microscopy to explore whether ISCs niches and the DEJ exhibit distinct mechanical properties. Our findings reveal that ISCs possess greater stiffness than other basal cells, a mechanical signature that diminishes with age. Additionally, the DEJ beneath ISCs shows higher stiffness than under other basal cells, providing ISCs with a specific mechanical environment, which also deteriorates during aging. Finally, sorting of ISCs based on MCSP expression allowed us to enrich a putative ISC-like subpopulation located above the dermal papillae. The study of ISCs mechanical signatures offers a promising approach for characterizing 3D skin models and understanding defects in skin renewal and wound healing.
Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon and environmental pollutant, has been implicated in the exacerbation of psoriasis, although the underlying molecular mechanisms remain unclear. In this study, we in...Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon and environmental pollutant, has been implicated in the exacerbation of psoriasis, although the underlying molecular mechanisms remain unclear. In this study, we investigated the role of BaP in inflammation, focusing on serum exosomes, using a mouse model of imiquimod (IMQ)-induced psoriasis. Topical BaP exposure aggravated psoriatic skin inflammation and increased the expression of aryl hydrocarbon receptor (AhR), CYP1A1, and proinflammatory cytokines in lesional skin. Serum exosomes from BaP + IMQ-treated mice enhanced cytokine expression in primary mouse keratinocytes. High-throughput miRNA profiling revealed that 81 and 91 miRNAs were upregulated in serum exosomes from IMQ- and BaP + IMQ-treated mice, respectively, compared to controls. Notably, mmu-miR-423-3p was the most upregulated in both groups, as validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Consistently, hsa-miR-423-5p was significantly elevated in circulating exosomes from psoriasis patients compared to healthy controls, confirmed by miRNA sequencing and qRT-PCR. KEGG pathway analysis linked hsa-miR-423-5p to the MAPK signalling pathway. Functionally, miR-423-5p triggered an increase in the expression of pro-inflammatory cytokines and oxidative stress in psoriatic keratinocytes. These findings suggest that BaP exacerbates psoriatic inflammation via AhR signalling and that serum exosomal miR-423 may serve as a biomarker for environmentally induced psoriasis exacerbation.
Lasalle C, Chang RC, Nowak NC
… +4 more, Wang Y, Giubellino A, Amber KT, Mansini AP
Exp Dermatol
· 2026 May · PMID 42126185
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Immune checkpoint inhibitors have transformed the treatment of advanced melanoma, yet many patients develop primary or acquired resistance. Although most work has focused on adaptive checkpoints (PD-1 and CTLA-4), accumu...Immune checkpoint inhibitors have transformed the treatment of advanced melanoma, yet many patients develop primary or acquired resistance. Although most work has focused on adaptive checkpoints (PD-1 and CTLA-4), accumulating evidence implicates innate immune suppression and stem-like, drug-resistant melanoma cell states. CD24, a small, heavily glycosylated glycosylphosphatidylinositol (GPI)-anchored surface protein, sits at the intersection of these processes and is emerging as a context-dependent biomarker and potential mediator of aggressive, therapy-resistant melanoma states. In this review, we synthesize evidence indicating that CD24 is both a tumour-intrinsic and tumour-extrinsic regulator in melanoma. We summarize the structure, glycosylation and regulation of CD24, then discuss its role in melanoma, supporting phenotypic plasticity, sustaining stem-like populations and promoting resistance to BRAF-targeted and cytotoxic therapies through SOX2/STAT3-linked programmes. We then examine the CD24-Siglec-10 axis as an innate immune checkpoint that suppresses macrophage and dendritic cell function, promotes immune-excluded 'cold' tumour microenvironments and may shape responses to immunotherapy among CD24+ melanoma cells. We highlight CD24 in tumour tissue, blood and extracellular vesicles as potential biomarkers of prognosis and pathway activity, and review CD24-axis interventions, including anti-CD24 antibodies, Siglec-10 antagonists and CD24-targeted CAR-T/CAR-NK cells, with rational combinations alongside PD-1/CTLA-4 blockade and MAPK-targeted therapy. We propose that biomarker-driven trials targeting this axis could open a new front in melanoma immunotherapy.
Exp Dermatol
· 2026 May · PMID 42124376
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Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disorder of the pilosebaceous unit, with multiple factors contributing to its onset, activity and progression. Alongside a predisposing genetic background,...Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disorder of the pilosebaceous unit, with multiple factors contributing to its onset, activity and progression. Alongside a predisposing genetic background, hormonal and microbiome alterations, dysregulation of innate and adaptive immune response, as well as environmental/epigenetic factors contribute to its immunopathogenic landscape. In the past years, translational investigations identified several distinct inflammatory networks, not only in the chronic but also in the early stages of disease, making them potential therapeutic targets. Emerging evidence underlies the important role of keratinocytes in the pathogenesis and progression of HS, acting not only as targets of inflammatory signaling pathways but also as active producers of pro-inflammatory cytokines, chemokines and effector molecules that may influence disease onset and activity. Despite these insights, different aspects of their involvement remain underexplored, necessitating further targeted research. This review aims to highlight the experimental evidence supporting the crucial role of keratinocytes in the inflammatory response and overall pathophysiology of HS.
Ultraviolet radiation (UVR) elicits complex, context‑dependent responses in the skin that reflect the balance between environmental stress and adaptive homeostatic mechanisms. The aryl hydrocarbon receptor (AhR) occupies...Ultraviolet radiation (UVR) elicits complex, context‑dependent responses in the skin that reflect the balance between environmental stress and adaptive homeostatic mechanisms. The aryl hydrocarbon receptor (AhR) occupies a central position in this interface, acting as a tunable environmental sensor that can mediate both photodamage and photoprotection depending on ligand type, timing and cellular context. In this editorial, we discuss recent findings demonstrating that melatonin pretreatment attenuates UVR-induced AhR expression and downstream inflammatory and photoaging‑associated responses in human skin ex vivo. We propose that these effects are best interpreted within a Yin-Yang framework of AhR signalling, in which transient, ligand‑specific activation initiates protective programmes followed by timely signal termination, rather than simple pathway inhibition. Melatonin and its metabolites may function as short‑lived AhR agonists that promote adaptive antioxidant and cytoprotective responses while preventing sustained, maladaptive activation. This conceptual refinement aligns with emerging insights into photo‑neuro‑immuno‑endocrine regulation of skin homeostasis and highlights AhR signalling as a flexible regulatory axis integrating ultraviolet exposure, endogenous metabolism and cutaneous defence mechanisms.
Exp Dermatol
· 2026 May · PMID 42108558
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UV radiation (UVR), a known skin-stressor causing inflammation, aging and carcinogenesis, activates the arylhydrocarbon receptor (AhR) and downstream molecules which are crucially involved in photo-induced skin damage. I...UV radiation (UVR), a known skin-stressor causing inflammation, aging and carcinogenesis, activates the arylhydrocarbon receptor (AhR) and downstream molecules which are crucially involved in photo-induced skin damage. In this study, the potent UV protector melatonin was investigated regarding UVR-mediated activation of AhR and downstream molecules including tumor suppressor p27, DNA double-strand break marker pH2AX, cyclooxygenase-2 (COX-2), mitogen-activated protein kinase-14 (MAPK14)/p38α, matrix metalloproteinase-2 (MMP2) and tissue inhibitor of matrix metalloproteinase-1 (TIMP1). They were studied in ex vivo human full-thickness skin irradiated with UVA/B light (0, 300 mJ/cm) 0 h and 24 h post UV exposure, comparing skin pre-incubated with or without melatonin. Protein expression was analysed by immunofluorescence staining, gene expression by real-time qPCR. UV exposure significantly up-regulated AhR (p < 0.0001), p27 (p < 0.001) and pH2AX (p < 0.0001) protein expression 0 h and 24 h post-irradiation which was significantly counteracted by melatonin (10 M) at both time points. Further, melatonin significantly reduced gene expression of AhR by 21.2% (p < 0.01), p27 by 24.8% (p < 0.01), COX-2 by 42.9% (p < 0.001), MAPK14 by 6.6% (p < 0.05) and MMP2 by 8.2% (p < 0.05), and caused a 10.2% (n.s.) TIMP1 reduction tendency 24 h post-irradiation. Thus, melatonin prevented UV-dependent expression of AhR and downstream regulators of AhR-mediated processes possibly related to inflammation, cellular aging and carcinogenesis on protein and gene level in UV-irradiated skin.