Acne vulgaris pathogenesis involves complex interactions between sebum hypersecretion, follicular hyperkeratinisation, microbial colonisation and inflammatory cascades. While the bacterial microbiome has been extensively studied, the role of the skin mycobiome, particularly lipophilic Malassezia species, remains less clearly defined in acne-prone sites. To evaluate evidence for skin mycobiome involvement in acne pathogenesis, a structured narrative review was conducted in PubMed/MEDLINE and PMC, synthesising findings from 14 cross-sectional studies involving 1650 participants from diverse geographic and ancestry backgrounds. Across sequencing and culture-based studies, Malassezia was the dominant fungal genus on healthy as well as acne-prone skin; species-level data most often identified M. restricta and M. globosa, with occasional reports of M. furfur. Although significant variations were observed in fungal abundance, discrepancies exist between studies due to differences in study design, sampling methods (surface swabs vs. comedone or pustule contents vs. pore strips), culture media (lipid-supplemented vs. standard), molecular target (ITS1 rDNA vs. other loci) and population demographics. Multiple sequencing studies did not detect significant fungal alpha/beta-diversity differences between acne and non-acne skin while confirming Malassezia species dominance. One study highlighted the potential underdiagnosis of Malassezia folliculitis in acne patients, suggesting that misdiagnosis may occur due to overlapping clinical presentations. Future studies should predefine primary outcomes, adjust for multiplicity, report sampling depth (surface vs. follicular), specify fungal rDNA region sequenced, use specific lipid-supplemented media for Malassezia isolation when culturing, co-profile bacteria and fungi, and add systematic clinical assessment of Malassezia folliculitis.

Palmoplantar inflammatory dermatoses, including hyperkeratotic palmoplantar eczema (HPE), palmoplantar psoriasis (PP) and palmoplantar pustulosis (PPP), present overlapping clinical features that complicate diagnosis and limit targeted therapy. This prospective observational study evaluated whether minimally invasive tape strip sampling, combined with targeted proteomics, can distinguish these conditions at a molecular level. Adults with HPE (n = 14), PP (n = 10), and PPP (n = 12) were enrolled, and tape strips from esional and non-lesional skin were analysed using the Olink Reveal panel (1034 proteins) with validation by MSD multiplex immunoassays. Differentially expressed proteins, pathway enrichment analysis, and protein-protein interaction analyses were conducted across the three diseases, and longitudinal analyses were conducted in a subset of patients with PP. Protein expression patterns showed partial separation of PPP from PP and HPE, whereas PP and HPE overlapped. Lesional samples across all three diagnoses exhibited increased expression of inflammatory proteins compared with non-lesional skin. PPP showed a distinct molecular profile from PP and HPE, with enriched pathways related to neutrophil degranulation, innate immune activation, and Th17-associated signalling networks centred on IL-17A and CXCL8. No proteins were significantly differentially expressed between PP and HPE lesions. PP and HPE showed overlapping interferon-associated chemokines CXCL10-11, consistent with a shared inflammatory module. Inflammatory protein levels decline with clinical improvement in longitudinal PP samples. Overall, tape strip-based targeted proteomics is a feasible approach for palmoplantar diseases, revealing a distinct inflammatory signature that differentiates PPP from PP and HPE, although discrimination between PP and HPE remains limited.

Hypertrophic scar is a pathological consequence of abnormal wound healing, marked by excessive fibroblast proliferation and extracellular matrix (ECM) accumulation. Macrophage-to-myofibroblast transformation (MMT) plays a key role in this process, but its regulatory mechanisms remain under investigation. This study found that microfibril-associated protein 4 (MFAP4) is significantly upregulated in mice scar tissue and is closely associated with the MMT process. In a mouse excision injury model, knockdown of MFAP4 in vivo macrophages using adeno-associated virus (AAV)-mediated RNA interference significantly reduced dermal thickening and disorganized collagen fibre deposition in mice scar tissues. Macrophage infiltration, expression of the myofibroblast marker α-SMA, and the proportion of MMT cells (F4/80[+]α-SMA[+]) were shown to be remarkably reduced. In vitro, TGF-β1 induces elevated MFAP4 expression within mouse-derived bone marrow-derived macrophages (BMDMs) and promotes MMT. MFAP4 knockdown inhibits TGF-β1-induced myofibroblast transformation and expression of ECM synthesis-related molecules (α-SMA, Col-I and Vimentin), while MFAP4 overexpression enhances these effects. Mechanistic studies suggest that MFAP4 regulates this process via the TGF-β/Smad3 signalling activation. MFAP4 promotes Smad3 phosphorylation (p-Smad3), and overexpression of Smad3 in MFAP4-knockdown mouse-derived BMDMs reverses the inhibitory effects of MFAP4 deficiency on MMT and ECM synthesis. These results reveal a key role for the MFAP4-TGF-β/Smad3 axis in regulating MMT-driven scar formation, providing novel insights into the mechanisms of hypertrophic scarring in mice and underlying therapeutic targets for clinical intervention.

Hidradenitis suppurativa (HS) is a prevalent, debilitating disease affecting ~1% of the population, with limited therapeutic options and poor long-term remission rates. HS arises from inflammation and destruction of apocrine-bearing hair follicles, suggesting a multifactorial pathology involving immune dysregulation and follicular dysfunction. Emerging treatment strategies largely center on immune suppression, with three FDA-approved therapies targeting inflammatory pathways. However, most patients fail to achieve durable remission. Genetic evidence increasingly implicates the hair follicle as a key contributor to HS pathogenesis. For example, genes that cause ectodermal dysplasias (EDs) have been implicated by common risk variants identified in genome-wide association studies (GWAS) and by rare variants in sequencing studies of rare ED syndromes that co-present with HS. EDs are Mendelian (i.e., single-gene) disorders that disrupt the development of ectodermal derivatives, including hair follicles and sweat glands. The enrichment of ED-associated genes in HS genetic studies, together with HS phenotypes observed in ED patients, supports a critical role for aberrant follicular development in HS pathogenesis. We propose that HS represents a spectrum of related diseases entities spanning immune dysregulation and hair follicle pathology, underscoring the need for biomarkers and refined disease classification to tailor treatment strategies. This perspective argues for broadening drug-development programs and insurance coverage for therapeutic strategies beyond immunomodulation to include follicle-targeted approaches.

Acral vitiligo responds less well to NB-UVB than non-acral disease, but site-specific immunologic changes during therapy are incompletely defined. The objective of this study was to compare NB-UVB-associated changes in T cell subsets and soluble mediators in acral versus non-acral vitiligo. Thirty patients with non-segmental vitiligo were enrolled. Ten underwent paired biopsies (acral and non-acral) before and after 6 months of NB-UVB for flow cytometry (Tregs, CD8+ T cells, CD8+CD45RO+ memory T cells, CD8+CD69+CD103+ TRM). Suction-blister fluid ELISA assessed IFN-γ-axis mediators (CXCR3, CXCL9, CXCL10, IFN-γ, IL-1β) in two separate groups: 10 treatment-naïve patients and 10 patients who had completed 6 months of NB-UVB therapy. Non-parametric tests used Benjamini-Hochberg FDR correction (pFDR). In paired biopsies (n = 10; CD8 n = 9), memory T cells decreased after NB-UVB in acral (4.38 [3.47-5.98] to 1.38 [0.73-2.21]; pFDR = 0.041) and non-acral lesions (5.23 [4.27-6.75] to 1.08 [0.48-2.54]; pFDR = 0.0039). TRM declined in acral (5.95 [3.17-7.41] to 0.65 [0.15-1.15]; pFDR = 0.0039) and non-acral sites (4.12 [2.50-5.57] to 0.69 [0.28-1.19]; pFDR = 0.0039). Tregs showed a site-divergent pattern: acral Tregs decreased (0.56 [0.41-0.75] to 0.08 [0.03-0.23]; pFDR = 0.0067) while non-acral Tregs increased (0.40 [0.24-0.61] to 0.95 [0.41-1.59]; pFDR = 0.0039). CD8+ T cells showed no change after correction. CXCL9 showed a non-significant decreasing trend (pFDR = 0.249); no ELISA marker remained significant after FDR correction. NB-UVB exerts a pronounced effect on cellular immunity (reductions in TRM and memory T cells) with limited cytokine suppression, with site-divergent Treg pattern.

Disentangling intrinsic (chronological) skin ageing from ultraviolet-driven photoaging remains challenging because most human skin single-cell studies are biassed towards sun-exposed sites and non-genital anatomy. Here, we profiled histologically normal human penile skin, a typically UV-shielded mucocutaneous niche, to characterise ageing-associated remodelling in a specialised cutaneous microenvironment. We analysed 137 880 cells from 13 healthy male donors (13-63 years) and identified 12 major cell types. Donor-aware compositional profiling revealed pronounced age-associated stromal depletion, driven by progressive loss of fibroblasts and pericyte/vascular smooth muscle cells. Whole-skin pseudo-bulk modelling across continuous age captured broad transcriptional drift towards senescence- and inflammation-related programmes alongside reduced extracellular matrix organisation and Wnt-associated maintenance pathways. Cell type-resolved pseudo-bulk analyses localised the strongest age-associated changes to stromal lineages. In fibroblasts, unsupervised temporal module analysis indicated a shift from matrix-supportive/regenerative programmes towards a pro-inflammatory, senescence-associated secretory phenotype-like state. Cross-compartment overlap further identified a 21-gene core module shared across epidermal, stromal, and immune compartments in older donors, consistent with coordinated tissue-wide remodelling. Together, these findings nominate stromal attrition and inflammatory fibroblast reprogramming as central features of ageing in human penile skin and provide a site-specific framework for distinguishing conserved intrinsic ageing modules from niche-shaped execution mechanisms. This UV-shielded genital reference offers a complementary baseline for interpreting intrinsic ageing signals across anatomically diverse skin sites.

Sweet syndrome (SS) is an autoinflammatory neutrophilic dermatosis characterized by abrupt-onset inflammatory skin lesions and systemic symptoms, yet its molecular pathogenesis remains incompletely defined. To delineate disease-specific inflammatory programmes, we performed NanoString-based transcriptomic analysis of SS skin lesions and compared them with healthy control skin and pyoderma gangrenosum, a related neutrophilic dermatosis. SS exhibited a distinct inflammatory transcriptional signature marked by robust upregulation of type I and II interferon-stimulated genes, including CXCL9, CXCL10, GBP1, GBP5, IFIT2 and IRF7, distinguishing SS from both control groups. Cell type deconvolution analysis revealed enrichment of dendritic cells, consistent with a prominent type I interferon-driven immune response. In parallel, SS lesions demonstrated altered immunoproteasome gene expression, with upregulation of immunoproteasome subunits PSMB8, PSMB9 and PSMB10 and downregulation of the constitutive subunit PSMB7 suggesting functional remodelling of proteasomal activity. Together, these findings support a model in which dendritic cell-driven interferon signalling promotes immunoproteasome remodelling and sustains neutrophilic inflammation in Sweet. This study identifies a prominent interferon signalling as a defining molecular feature of SS and highlights potential therapeutic opportunities within the interferon-JAK/STAT and proteasome pathways.

Dermal adipocytes have unique features different from visceral and subcutaneous adipocytes. Their cyclic remodelling is coupled with hair follicle (HF) cycling: expansion in the anagen and reduction in the catagen stages. Secreted Ly6/uPAR related protein 2 (SLURP2) is a non-neuronal transmitter and a ligand of both nicotinic and muscarinic acetylcholine receptors. It is upregulated in psoriatic lesions. Mouse SLURP2-deficient mice exhibit reduced adiposity and plasma cholesterol levels, in addition to palmoplantar keratoderma. However, the effects of SLURP2 on adipocytes remain unexplored. Here, we demonstrated that SLURP2 regulates murine dermal adipocyte size independently of HF cycling and upregulates interleukin (IL)-23 gene expression following intradermal injection of recombinant human SLURP2-Fc protein (rSLURP2) and phosphate-buffered saline (control) at different dorsal sites of C57BL/6J mice after depilation. SLURP2 enlarged dermal adipocytes independently of HF cycles by inhibiting sterol regulatory element-binding protein-1, a transcription factor involved in cholesterol and fatty acid synthesis, which leads to the activation of cholesterol synthesis followed by expansion of the plasma and lipid droplet membrane. Immunohistochemical staining of paired mirror sections revealed a statistically significant increase in the ratio of IL-23-producing macrophages in the dermal adipose tissue of rSLURP2-injected skin compared with the control. Furthermore, IL-23p19 gene expression was significantly upregulated in rSLURP2-treated skin. Taken together with the previous findings, the present study showed that SLURP2 has inflammatory and metabolic effects. Dermal adipose tissues may serve as a source of IL-23 in psoriatic lesions.

Psoriasis is a complex chronic inflammatory and autoimmune disease; therefore, reliable and human-relevant animal models are essential for preclinical drug testing and mechanistic studies. SKH-1 mice, which lack functional hair follicles and display a thickened epidermis that more closely resembles human skin than that of C57BL/6 mice, represent a potential psoriasis model, but their suitability remains uncertain. In this study, proliferation, barrier function, differentiation, and inflammatory responses were assessed in the imiquimod (IMQ)-induced dermatitis model of SKH-1 mice using qRT-PCR, immunofluorescence, and flow cytometry. Transcriptomic profiling via RNA sequencing was performed on total RNA from lesional and non-lesional skin of IMQ-induced SKH-1 mice, IMQ-induced C57BL/6 mice, and human psoriatic skin. A psoriasis-like mouse model was also established in SKH-1 mice to evaluate its utility for recurrence studies. The results showed that the IMQ-induced SKH-1 mouse model exhibited hyperproliferation, hypodifferentiation, barrier disruption, and excessive inflammatory responses similar to human psoriasis. Transcriptomic analysis further highlighted the advantages and complementarity of this model in studying psoriasis pathogenesis, and the established recurrence model provided a suitable tool for investigating the mechanisms of psoriasis recurrence. This study compared the transcriptomic signatures of lesional skin between IMQ-induced SKH-1 and C57BL/6 mice and demonstrated that the SKH-1 model can recapitulate vascular dysregulation and disease recurrence, indicating that it serves as a valuable complementary tool for probing psoriasis pathogenesis.

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 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 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.