Chronic exposure to ultraviolet B (UVB) radiation induces excessive reactive oxygen species (ROS) production in dermal fibroblasts, leading to cellular senescence and skin photoaging. Ageing skin is characterised by disr...Chronic exposure to ultraviolet B (UVB) radiation induces excessive reactive oxygen species (ROS) production in dermal fibroblasts, leading to cellular senescence and skin photoaging. Ageing skin is characterised by disruption of the immune microenvironment, including impaired macrophage polarisation and reduced M2 macrophage activity. However, the contribution of M2 macrophages to fibroblast photoaging remains incompletely understood. Here, we investigated whether M2 macrophages attenuate UVB-induced fibroblast senescence through ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2)-dependent lysophosphatidic acid (LPA)signalling. UVB-induced L929 fibroblasts were treated with conditioned media derived from polarised RAW264.7 macrophages, with or without ENPP2 silencing. UVB exposure induced marked senescence, oxidative stress, and mitophagy impairment, whereas conditioned medium from M2 macrophages significantly alleviated these effects compared with M1-derived conditioned medium. Notably, ENPP2 depletion in M2 macrophages substantially reduced these protective effects. M2 macrophage-derived conditioned medium contained elevated LPA levels and restored UVB-suppressed LPAR1 and LPAR3 expression in fibroblasts. Pharmacological inhibition of LPAR1/3 attenuated the protective effects of M2 macrophages, while exogenous LPA supplementation restored these effects under ENPP2-deficient conditions. These changes were associated with enhanced PINK1/Parkin-related mitophagy signalling and reduced oxidative stress. Collectively, these findings identify M2 macrophage-derived ENPP2/LPA signalling as a critical paracrine mechanism that mitigates UVB-induced fibroblast photoaging.
The rapid advancement of human-relevant in vitro skin models has been driven by increasingly stringent regulatory restrictions on animal testing and the growing recognition that conventional animal and two-dimensional ce...The rapid advancement of human-relevant in vitro skin models has been driven by increasingly stringent regulatory restrictions on animal testing and the growing recognition that conventional animal and two-dimensional cell culture systems fail to accurately predict human skin biology and clinical outcomes. Three-dimensional reconstructed human skin models, ex vivo human skin platforms, and next-generation bioengineered systems have been recognized as critical tools for dermatological research, cosmetic safety assessment, and pharmaceutical development. This review focuses on commercially available in vitro human skin models currently used in regulatory and research settings, as well as emerging technologies under active development. We provide an overview of reconstructed human epidermis and full-thickness skin equivalents, functional variants incorporating pigmentation and microbiome support, and ex vivo human skin models derived from surgical tissues. Additionally, we discuss cutting-edge platforms, including vascularized and perfused skin models, immune-competent skin constructs, organoid-based appendage-containing models, and microbiome-integrated platforms. Furthermore, we highlight current limitations, regulatory gaps, and future directions for standardization, scalability, and clinical translation. Collectively, advanced human skin models are expected to significantly enhance dermatological research by enabling predictive, ethical, and mechanistically informative testing strategies that bridge the gap between in vitro experimentation and clinical outcomes.
Palmoplantar keratoderma (PPK) is a heterogeneous group of skin diseases, characterised by excessive keratinization and hyperplasia of the palms and soles. However, accurate molecular diagnosis remains challenging due to...Palmoplantar keratoderma (PPK) is a heterogeneous group of skin diseases, characterised by excessive keratinization and hyperplasia of the palms and soles. However, accurate molecular diagnosis remains challenging due to the low prevalence of hereditary forms. This study analysed the phenotype and genotype distribution in a large cohort of Chinese patients with PPK, aiming to clarify the genetic aetiology and genotype-phenotype correlations. We further validated the pathogenicity of biallelic SERPINA12 variants identified in four patients. A total of 424 patients with PPK were enrolled from 2010 to 2023. Of these, 97.6% (414/424) presented with diffuse PPK, predominantly Nagashima-type PPK (NPPK), with rare cases of Olmsted, Meleda and Bothnia types. Focal PPK accounted for 1.4%, with less than 1% for striate and punctate types, respectively. Genetic testing was performed in 380 patients. Overall, 328 patients harboured pathogenic or likely pathogenic (P/LP) variants to achieve definite molecular diagnosis; none carried only variants of uncertain significance (VUS) and the remaining 52 patients had no candidate disease-associated variants identified. All patients underwent testing with an in-house customised SERPINB7 gene hotspot panel test for c.796C>T, c.522_523insT, c.806_818delinsT and c.650_653delCTGT variants. In 80% (304/380) patients, hotspot variants in SERPINB7 were identified, with c.796C>T (77%) and c.522_523insT (16%) being the most frequent. Patients not diagnosed with a hotspot variant further underwent whole-exome sequencing (WES), which identified confirmed pathogenic (P) or likely pathogenic (LP) variants in TRPV3 (c.1246C>T, c.1703G>A, c.1247G>A), AQP5 (c.530 T>A, c.367A>T), SLURP1 (c.154A>G), KRT9 (c.1373 T>C), KRT6A (c.947G>C) and KRT16 (c.379C>T). In addition, three recurrent SERPINA12 variants were identified, enriching the gene spectrum of diffuse PPK. This study established the largest cohort of patients with SERPINB7 variants reported to date, identifying that NPPK is the predominant subtype among Chinese populations. Variants in SERPINA12 are likely correlated with diffuse palmoplantar keratoderma, consistent with the clinical manifestations of NPPK. Additionally, a diagnostic panel targeting ancestral SERPINB7 founder variants would markedly improve the molecular diagnostic yield in Chinese patients.
This study aims to assess the adverse event profile of apremilast using FDA Adverse Event Reporting System (FAERS) data to identify potential safety risks and support clinical use. FAERS data from Q1 2014 to Q1 2024 were...This study aims to assess the adverse event profile of apremilast using FDA Adverse Event Reporting System (FAERS) data to identify potential safety risks and support clinical use. FAERS data from Q1 2014 to Q1 2024 were analysed. Adverse drug events (ADEs) related to apremilast were extracted and evaluated using four signal detection methods: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). A total of 122 287 apremilast-related AE reports, encompassing 238 215 adverse reactions across 24 System Organ Classes (SOCs) and 60 apremilast-induced AE signals, were identified. Gastrointestinal disorders, skin and subcutaneous tissue disorders, and musculoskeletal and connective tissue disorders were the most frequently reported SOCs. Common Preferred Terms (PTs) included diarrhoea, nausea, and headache. Notably, some adverse effects not listed in the drug package insert were found, such as multiple allergic reactions and tumour signals. This study identified significant disproportionality signals for ADEs reported with apremilast, particularly concerning gastrointestinal reactions, psychiatric disorders, and infections. While these findings do not establish causality, they offer valuable real-world insights that underscore the importance of continued clinical monitoring and warrant further pharmacoepidemiologic investigation.
Despite the recognized association between bullous pemphigoid (BP) and psoriasis, the clinical and immunological profiles, and inflammation patterns of coexistence remain undefined. We therefore conducted a retrospective...Despite the recognized association between bullous pemphigoid (BP) and psoriasis, the clinical and immunological profiles, and inflammation patterns of coexistence remain undefined. We therefore conducted a retrospective cohort study of 140 BP patients without psoriasis (BP alone group) and 24 BP patients with comorbid psoriasis (BP-PsO group) to characterise these features. Average age of BP onset was significantly lower in the BP-PsO group, compared with the BP alone group (median [IQR]: 67.00 [58.00-75.75] years vs. 75.00 [64.00-82.00] years) (p = 0.021). In the BP-PsO group, 21 patients (87.5%) had coexisting active psoriatic plaques and BP lesions. The overall disease activity of BP was comparable between the BP-PsO and BP alone groups, both showing typical BP immunological features. Serum IL-17A level was significantly elevated in the BP-PsO group (median [IQR]: 18.29 [10.39-43.50] pg/mL), compared with the BP alone group (median [IQR]: 10.36 [9.16-12.11] pg/mL) and psoriasis alone groups (median [IQR]: 11.65 [10.10-12.78] pg/mL), and correlated with disease activity. Flow cytometry confirmed enhanced IL-17A response in peripheral blood mononuclear cells from the BP-PsO group, with an elevated proportion of CD4 IL-17A cells and IL-17A T follicular helper cells versus corresponding controls. IL-13 was comparably elevated in both the BP-PsO and BP alone groups, relative to psoriasis alone group and healthy controls. In a representative case, inhibition of IL-17A led to concurrent remission of both diseases. BP with psoriasis shares foundational features with idiopathic BP, but represents a distinct clinical entity characterised by a predominant IL-17A signature, highlighting its potential as a therapeutic target.
Icariin, the principal active compound of Epimedium species used in traditional East Asian medicine, exhibits anti-inflammatory and lipid-regulating effects. However, its effects on human sebocytes and dermal fibroblasts...Icariin, the principal active compound of Epimedium species used in traditional East Asian medicine, exhibits anti-inflammatory and lipid-regulating effects. However, its effects on human sebocytes and dermal fibroblasts, which could be implicated in the management of acne and atrophic scarring, remain unexplored. This study aimed to evaluate the effects of icariin on human sebocytes, keratinocytes and dermal fibroblasts. Icariin's effects on cell viability, lipid synthesis, inflammation, abnormal keratinization and extracellular matrix (ECM) synthesis were assessed using human SEB-1 sebocytes, HaCaT keratinocytes and Detroit 551 fibroblasts. Icariin modestly promoted the proliferation of SEB-1 sebocytes, HaCaT keratinocytes and Detroit 551 fibroblasts. It reduced mRNA levels of lipogenic and proinflammatory markers in SEB-1 sebocytes and HaCaT keratinocytes. Icariin counteracted arachidonic acid-induced lipogenesis in SEB-1 sebocytes in parallel with modulation of the insulin-like growth factor 1 receptor/Akt signalling pathway. In Detroit 551 fibroblasts, it enhanced ECM protein expression and reduced the expression of ECM-degrading enzymes, accompanied by upregulation of platelet-derived growth factor receptor and latent transforming growth factor β binding protein 4. In conclusion, this study demonstrates that icariin modulates key pathophysiological processes of acne and promotes ECM synthesis, suggesting its potential as a novel therapeutic agent for managing both acne and atrophic acne scars.
Necroptosis, a form of programmed cell death, promotes inflammation in immune-mediated diseases, but its role in alopecia areata (AA) remains unclear. In this study, we investigated necroptosis-related signatures in AA u...Necroptosis, a form of programmed cell death, promotes inflammation in immune-mediated diseases, but its role in alopecia areata (AA) remains unclear. In this study, we investigated necroptosis-related signatures in AA using integrated transcriptomic and histological analyses. Four bulk RNA-seq datasets from the GEO database, comprising 191 scalp samples from AA patients and healthy controls, were analysed by ssGSEA and GSEA to assess necroptosis-related signatures. To address the cellular heterogeneity inherent in bulk RNA data, we further performed single-cell RNA-sequencing (scRNA-seq) to investigate cell-specific mechanisms, and immunofluorescence staining of scalp biopsies was conducted to validate the expression and cellular localisation of key necroptosis-related markers. Necroptosis-related scores were significantly higher in AA than in controls, correlated with disease severity and decreased after JAK/TYK2 inhibitor therapy. At single-cell resolution, a macrophage subset (IL4I1 macrophages_1) showed the strongest necroptosis-related signal and was associated with enhanced macrophage-fibroblast communication involving TGFβ, ITGB2 and GAS6 signalling, suggesting perifollicular microenvironmental remodelling. Immunofluorescence further supported increased necroptosis-associated signalling and macrophage enrichment in AA lesions. Together, these findings suggest that macrophage-associated necroptosis-related programmes may represent a disease-associated inflammatory component in AA and support further mechanistic investigation of necroptosis-associated pathways in this disease.
Zhen Q, Yin N, Chen W
… +29 more, Qu G, Yan S, Wang Y, Li Z, Bai B, Lv C, Zhang J, Hu H, Jiang Q, Kang X, Xu Y, Lu Y, Zhao J, Wu S, Li S, Chen X, Qi R, Lin X, Han J, Lu Y, Shi J, Qiu Y, Fan Y, Li S, Li F, Li Y, Gao X, Han Y, Sun L
Psoriasis is a recurrent autoimmune disease. No biological factor that is associated with the risk of psoriasis has been definitively identified. The potential role of the immunogen double-stranded (ds)DNA as a trigger o...Psoriasis is a recurrent autoimmune disease. No biological factor that is associated with the risk of psoriasis has been definitively identified. The potential role of the immunogen double-stranded (ds)DNA as a trigger of and biomarker for psoriasis warrants exploration. This multicentre case-control study included 3 069 patients with psoriasis and 7 041 healthy controls from 12 regions in China. The associations of the serum dsDNA level with the psoriasis risk and severity were analysed in the overall population. The serum dsDNA level was significantly higher in patients than in controls. Each 0.1 ng/mL increase in serum dsDNA was significantly associated with increased odds of psoriasis (adjusted odds ratio, 1.45; 95% confidence interval, 1.40-1.48; p < 0.001). The optimal serum dsDNA cutoff value for the diagnosis of psoriasis was 1.11 ng/mL, with 61.6% sensitivity and 74.8% specificity. A significant dose-response relationship was observed between the serum dsDNA level and the risk of psoriasis-associated morbidity when using the optimal dsDNA cutoff value as the reference. Serum dsDNA levels were positively associated with higher PASI and BSA scores and the severity of psoriasis. These findings suggest that serum dsDNA level is strongly associated with psoriasis morbidity and severity.
Scarring alopecia remains a major clinical challenge, characterized by irreversible hair follicle (HF) loss and replacement by scar tissue. Wound-induced hair follicle neogenesis (WIHN) serves as a model in which HFs can...Scarring alopecia remains a major clinical challenge, characterized by irreversible hair follicle (HF) loss and replacement by scar tissue. Wound-induced hair follicle neogenesis (WIHN) serves as a model in which HFs can regenerate following skin wounding. In this study, we characterized the cellular landscape associated with differences in regenerative capacity between small wound (SW) and large wound (LW) tissues at a late regenerative stage (post-wounding day 22, PWD22), a time point at which newly formed hair follicles are already present. Using single-cell RNA sequencing (scRNA-seq), we profiled re-epithelialized wound tissues from SW and LW conditions and identified major cutaneous cell populations, including keratinocytes and fibroblasts. Keratinocytes were further categorized into 8 subpopulations, among which infundibular basal keratinocytes (INFU basal KCs) were increased in LW compared with SW tissues, as validated by immunofluorescence (IF) staining. Pseudotime analysis indicated differences in the temporal expression pattern of the INFU basal KC marker Fst between SW and LW conditions. Cell-cell communication between keratinocytes and fibroblasts showed that extracellular matrix (ECM)-receptor interactions were markedly enriched, while Masson's trichrome staining revealed decreased collagen content in LW. IF staining showed increased COL6A3 expression and decreased FN1 expression in LW tissues. Taken together, our study provides a descriptive single-cell atlas of late-stage wound tissues with differing regenerative outcomes, indicating differences in keratinocyte composition, transcriptional states, and intercellular communication. Collectively, our findings offer a resource for understanding cellular heterogeneity associated with WIHN and may inform future studies aimed at elucidating the mechanisms of hair follicle regeneration in cutaneous repair.
Hair loss is a common condition with limited therapeutic options, and bacterial extracellular vesicles have recently emerged as potential bioactive mediators in skin biology. Here, we investigated whether an extracellula...Hair loss is a common condition with limited therapeutic options, and bacterial extracellular vesicles have recently emerged as potential bioactive mediators in skin biology. Here, we investigated whether an extracellular vesicle-enriched preparation obtained from Sphingomonas olei, a bacterium isolated from healthy human skin (hereafter SoEVs), influences human hair-growth-related responses and whether these effects are associated with Wnt/β-catenin-related signalling. SoEVs were non-cytotoxic to human dermal papilla (DP) cells and upregulated the hair-growth-related factors IGF1 and VEGFA. In DP cells, SoEV treatment was accompanied by increased levels of phosphorylated AKT and GSK-3β, and total β-catenin, alongside the induction of canonical Wnt readouts LEF1 and AXIN2. In ex vivo cultured human hair follicles, SoEVs promoted hair shaft elongation, counteracted shaft thinning and increased the number of Ki-67-positive cells around the DP. Together, these findings suggest that SoEVs may support human hair-growth-related responses in association with Wnt/β-catenin-related signalling, warranting further mechanistic and in vivo investigation.
Rieger-Molitor L, Maj C, Redler S
… +7 more, Gossmann Y, Ripke S, Pethukova L, Christiano AM, Nöthen MM, Basmanav FB, Betz RC
Exp Dermatol
· 2026 Jun · PMID 42311022
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Alopecia areata (AA) is a common T-cell mediated autoimmune disorder, which leads to sudden, non-scarring hair loss. An association between hair pigmentation and AA pathogenesis has long been postulated. Recent epidemiol...Alopecia areata (AA) is a common T-cell mediated autoimmune disorder, which leads to sudden, non-scarring hair loss. An association between hair pigmentation and AA pathogenesis has long been postulated. Recent epidemiological evidence supports this link, indicating that individuals with darker hair colours have a higher risk of AA, while those with lighter hair colours exhibit a lower risk. This study aimed to investigate whether a shared genetic basis between hair colour determination and AA risk underlies this observation. To explore this, we analysed data from our AA genome-wide association study (GWAS) of 16 310 Caucasians from the US and Central Europe and a recently published GWAS of hair colour that involved 343 234 UK Biobank participants. Genetic correlations between the two traits were investigated using both polygenic risk score and linkage disequilibrium score regression (LDSC) analyses. No evidence was found for a strong, broadly shared genetic component for hair colour and AA. However, a suggestive weak inverse association with genetically predicted blond hair and AA risk was observed. Given the modest sample size of the AA-GWAS (~4100 cases), these findings are likely underpowered and should be interpreted as exploratory and hypothesis-generating, warranting replication in larger, independent cohorts.
Hsu-Rehder HH, Glocker C, Aldrian C
… +7 more, Dikici E, Wilde GS, Stavila M, Jonca N, Kollár B, Eisenhardt SU, Fischer J
Exp Dermatol
· 2026 Jun · PMID 42295031
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Autosomal recessive nonsyndromic epidermal differentiation disorders (AR-nEDDs), also known as autosomal recessive congenital ichthyosis (ARCI), are rare genetic skin diseases that lack curative treatments and can only b...Autosomal recessive nonsyndromic epidermal differentiation disorders (AR-nEDDs), also known as autosomal recessive congenital ichthyosis (ARCI), are rare genetic skin diseases that lack curative treatments and can only be managed symptomatically. Their study is hampered by the limited availability of biological samples and donor tissues. Artificial skin models offer a valuable alternative for experimental research. Here, we generated epidermal skin equivalents (ESE) using primary keratinocytes from patients with AR-nEDDs carrying pathogenic variants in ALOX12B, CYP4F22, and CERS3, as well as immortalized N/TERT-2G cells. Whereas primary cells undergo senescence, N/TERT-2G cells offer a promising alternative to overcome this limitation. Histological staining and qPCR were applied to assess key epidermal proteins and AR-nEDD-related gene expression in patient- and control-derived models. Patient-derived ESE reproduced the major histopathological features and protein expression patterns characteristic of AR-nEDDs. In contrast, N/TERT-2G-based models showed earlier expression of 12R-LOX, CYP4F22, and CERS3 proteins in epidermal layers compared to healthy donor equivalents. These findings suggest that N/TERT-2G cells represent a reproducible platform for future gene-editing approaches of modelling epidermal differentiation disorders. However, as they do not inherently carry pathogenic variants, they are particularly suitable for gene-editing approaches such as CRISPR/Cas9-mediated disease modelling. Conversely, patient-derived keratinocyte models remain indispensable for validating disease mechanisms and evaluating therapeutic strategies.
The dermal papilla (DP) is essential to hair follicle development and regeneration. Isolation of human DPs still largely depends on manual microdissection and human DP cells (DPCs) lose their intrinsic properties in vitr...The dermal papilla (DP) is essential to hair follicle development and regeneration. Isolation of human DPs still largely depends on manual microdissection and human DP cells (DPCs) lose their intrinsic properties in vitro. Establishing a culture condition that maintains the biological properties of DPCs allows for identification of cell surface markers that enable cell sorting of living human DPCs. A new DPC culture condition was developed using the combination of a WNT activator, CHIR99021, and recombinant FGF9 (CH + F9). Global gene expression profiling and bioinformatic analyses of DPCs grown under this condition were conducted to identify DPC surface markers enabling live DPC isolation. Compared to a conventional culture condition, CH + F9 increased the expression of the representative DPC biomarkers WNT5A, LEF1 and BMP4 by 3.4-, 3.8- and 60.5-fold (p < 0.01) and better maintained their expression levels after long-term serial passaging. Aggregated CH + F9-treated DPCs unevenly upregulated DP biomarkers further, suggesting that highly potent DPCs can be enriched using a marker for such cells. Bioinformatics analysis of CH + F9-treated and control DPCs identified cell marker candidates, including roundabout guidance receptor 2 (ROBO2). Importantly, ROBO2 DPCs expressing the representative DP biomarkers WNT5A, VCAN, NOG were successfully sorted from mixed cell suspensions of keratinocytes, fibroblasts and DPCs mimicking enzymatically dissociated human skin. These findings suggest that the new culture condition and cell surface marker for human DPCs established in this study provide useful tools for drug discovery and regenerative medicine to address hair loss diseases.
Vagus nerve stimulation (VNS) modulates systemic inflammation through the cholinergic anti-inflammatory pathway, but its effects on cutaneous inflammatory diseases remain unexplored. We investigated whether invasive VNS...Vagus nerve stimulation (VNS) modulates systemic inflammation through the cholinergic anti-inflammatory pathway, but its effects on cutaneous inflammatory diseases remain unexplored. We investigated whether invasive VNS could reduce clinical inflammation and proinflammatory cytokines in murine models of psoriasis and atopic dermatitis (AD). C57BL/6 mice received imiquimod 5% cream to induce psoriasiform inflammation, while NC/Nga mice received 2,4-dinitrochlorobenzene (DNCB) to induce AD-like inflammation. Acute invasive VNS (5 Hz/5 ms for 5 min) or sham procedures were performed 6 or 24 h before sacrifice. Cutaneous cytokine levels were assessed by immunoblotting and immunofluorescence staining, while systemic inflammation was evaluated by analyzing splenic and plasma cytokines. VNS reduced TNF-α and IL-6 in imiquimod-treated skin at both 6- and 24-h post-stimulation (TNF-α/6 h: 63%, p < 0.01; IL-6/6 h: 63%, p < 0.01; TNF-α/24 h: 69%, p < 0.001; IL-6/24 h: 60%, p < 0.05). In DNCB-treated skin, VNS decreased TNF-α, IL-1β, and IL-6 at 24 h post-stimulation (TNF-α/24 h: 68%, p < 0.001; IL-1β/24 h: 48%, p < 0.05; IL-6/24 h: 66%, p < 0.01). VNS altered cutaneous CD11b-positive macrophage distribution patterns and reduced splenic cytokine levels (TNF-α and IL-1β) in the psoriasis model (TNF-α/6 h: 73%, p < 0.001; 24 h: 46%, p < 0.05) (IL-1β/6 h: 48%, p < 0.01; 24 h: 41%, p < 0.05) while plasma TNF-α decreased in the AD model (24 h: 32%, p < 0.01). This study provides the first evidence that VNS reduces proinflammatory cytokines in inflammatory skin diseases, supporting clinical translation for dermatological applications.
Zhu A, Yang L, Lai S
… +3 more, Yang F, Tsuruta D, Katayama I
Exp Dermatol
· 2026 Jun · PMID 42272107
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The circadian clock regulates multiple physiological processes in the skin, including local hormone synthesis and pigmentation. However, how circadian regulation interacts with epidermal endocrine signalling in melanocyt...The circadian clock regulates multiple physiological processes in the skin, including local hormone synthesis and pigmentation. However, how circadian regulation interacts with epidermal endocrine signalling in melanocytes remains unclear. In this study, we investigated whether core circadian regulators influence melanogenesis in human melanocytes and explored their potential link to epidermal endocrine factors and pigmentary disease. Primary normal human epidermal melanocytes were analysed following siRNA-mediated knockdown of the core clock genes basic helix-loop-helix ARNT-like protein 1 (BMAL1) and CLOCK circadian regulator (CLOCK). Silencing either gene significantly reduced melanin synthesis and altered the expression of hormone-related factors. Notably, expression of the vitamin D-metabolizing enzyme CYP27A1 was markedly decreased after BMAL1 or CLOCK knockdown, changes that were associated with reduced melanogenic activity. Consistently, immunohistochemical analysis revealed diminished CYP27A1 expression in melanocytes within vitiligo lesions. These findings demonstrate that disruption of circadian clock regulators impairs melanogenesis and is accompanied by alterations in vitamin D-related components. Our results suggest that circadian regulation may modulate pigmentation partly through effects on vitamin D metabolism, providing new insight into the mechanisms underlying pigmentary disorders.
Dysregulated type I interferon (IFN-I) signalling is implicated in the pathogenesis of several systemic autoimmune conditions, collectively termed type I interferonopathies. Emerging evidence suggests that aberrant IFN-I...Dysregulated type I interferon (IFN-I) signalling is implicated in the pathogenesis of several systemic autoimmune conditions, collectively termed type I interferonopathies. Emerging evidence suggests that aberrant IFN-I pathway activity may similarly contribute to certain autoimmune dermatoses, namely granuloma annulare (GA), lichen planus (LP), cutaneous sarcoidosis (CS) and morphea. We sought to investigate this association using large, real-world cohorts, with type I interferonopathies serving as proxies for IFN-I-driven inflammation. Four retrospective cohort studies were conducted in parallel using the TriNetX Global Collaborative Network. Patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren's disease (SjD) and dermatomyositis (DM) were 1:1 propensity score-matched to healthy controls (HCs), and relative risks (RRs) for developing GA, CS, LP and morphea were calculated. Sensitivity analyses compared each interferonopathy cohort to patients with gout and ankylosing spondylitis, rheumatologic conditions not mediated by IFN-I pathways. Increased risk of morphea and LP was observed across all four interferonopathy cohorts relative to HCs. Patients with SLE, SSc and SjD had an increased risk of developing CS. GA risk was significantly increased only among patients with SLE and DM. Sensitivity analyses were broadly corroborative. These findings reveal consistent associations between type I interferonopathies and subsequent development of LP, CS and morphea. The results of these analyses are hypothesis-generating and complement existing evidence of an IFN-I mediated pathogenesis for these dermatoses. Prospective studies employing large, representative cohorts paired with transcriptomic and proteomic technologies for mechanistic confirmation are warranted.