Therapeutic strategies for malignant tumors have advanced substantially, and antibody–drug conjugates (ADCs) now enable selective delivery of cytotoxic payloads to tumor cells. Enfortumab vedotin (EV) is a nectin-4–directed ADC composed of a fully human monoclonal antibody against nectin-4 conjugated, via a protease-cleavable linker, to the microtubule-disrupting agent monomethyl auristatin E. EV has demonstrated robust antitumor activity in urothelial carcinoma and is being investigated in other nectin-4–expressing tumors. Because nectin-4 is expressed in keratinocytes and cutaneous appendages, cutaneous adverse events are among the most frequent toxicities. EV-related cutaneous toxicity represents an on-target, mechanism-based toxicity that is distinct from the cutaneous adverse events associated with conventional cytotoxic chemotherapy. This review summarizes the molecular structure and function of nectin-4 and the clinical and histopathologic features of EV-related cutaneous toxicity and discusses current approaches to management. By integrating mechanistic insights from experimental studies with clinical and histopathologic observations, this review provides a translational framework to support optimal recognition and management of EV-related cutaneous toxicity.
Background Langerhans cells (LCs) consist of embryonically derived resident LCs (rLCs) and monocyte-derived LCs (moLCs), yet how distinct LC subsets migrate and function during psoriatic skin inflammation remains incompletely understood. Objective To characterize the migratory behavior and immunological roles of rLCs and moLCs in imiquimod (IMQ)-induced skin inflammation. Methods We examined LC subset dynamics in an IMQ-induced murine dermatitis model using flow cytometry and immunofluorescence. To dissect subset-specific functions, moLCs were selectively ablated in Cd207fl/flLyz2Cre conditional knockout mice, while rLCs were depleted using Langerin-DTR mice. Skin inflammation severity, T cell profiles, and PD-L1 expression were assessed. Human psoriatic lesions (mild vs. moderate-to-severe) were analyzed by multiplex immunofluorescence. Results IMQ treatment induced progressive moLC accumulation in skin lesions (both number and proportion increased), while rLCs diminished locally but accumulated significantly in draining lymph nodes with upregulated CCR7 expression. Genetic ablation of moLCs reduced epidermal hyperplasia, ear thickness, and IL-17/IL-22-producing CD4+ T cells and γδ T cells in lesions. Conversely, rLC depletion exacerbated dermatitis, reduced PD-L1 expression in lymph node LCs, and enhanced γδ T cell activation both locally and systemically. In human psoriatic lesions, moLC density correlated with local lesion severity at the histological level, while CCR7 expression was predominantly detected on rLCs rather than moLCs. Conclusion rLCs and moLCs display distinct migratory behaviors and exert divergent immunological functions during IMQ-induced skin inflammation. Lesion-retained moLCs are associated with local inflammatory responses, whereas lymph node-migratory rLCs are linked to immunoregulatory activity.
Background Dermal stem cells (DSCs) act as fibroblast progenitors essential for maintaining skin structure and wound healing. However, the molecular mechanisms governing DSC maintenance remain unclear. Objective This study aimed to elucidate the factors involved in DSC maintenance. Methods Age-related changes in CD271-positive DSC count were determined by immunohistochemical staining. Primary dermal cells derived from participants categorized as either DSC-rich or DSC-poor underwent proteomic analysis. The expression of superoxide dismutase 3 (SOD3) in the dermis and DSCs was evaluated using immunostaining and quantitative RT-PCR (qRT-PCR). Additionally, a knockdown experiment was conducted to clarify SOD3 involvement in DSC maintenance. Results DSC count decreased with age. In proteomic analysis, DSC-rich dermal cells displayed high SOD3 expression. Furthermore, DSCs had significantly higher SOD3 expression than nonstem cells, contributing to higher SOD3 levels in DSC-rich dermis. Inducing the differentiation of DSCs into fibroblasts decreased SOD3 gene expression. SOD3 knockdown in DSCs increased reactive oxygen species (ROS) levels and DNA damage, causing downregulation of DNA repair genes and stem cell marker genes and upregulation of fibroblast marker genes. However, treatment with recombinant SOD3 protein or ascorbic acid resolved these phenotypes. Conclusion SOD3 is a protein essential for maintaining DSCs. The findings of this study offer a new perspective on the molecular mechanisms underlying skin aging and suggest SOD3 as a potential therapeutic target.
BACKGROUND:Autosomal recessive woolly hair (ARWH) is a congenital hair disorder characterized by excessively curled scalp hair with limited growth. One of the causative genes, LIPH encoding PA-PLA1α, is involved in a lipid mediator-dependent signaling, and loss-of-function variants in C3orf52 encoding the transmembrane protein associated with PA-PLA1α, have recently been implicated in ARWH. The pathogenic mechanisms for ARWH, however, remain incompletely understood. OBJECTIVE:To characterize LIPH gene-variants responsible for ARWH and to further clarify the molecular properties of C3orf52. METHODS:Wild-type and five mutant PA-PLA1α (p.W108R, p.H205R, p.C246S, p.H248N, and p.V437Gfs*4), as well as wild-type C3orf52, were overexpressed in cultured cells, and a series of expression and functional analyzes were performed. C3orf52 expression was additionally assessed in human scalp skin sections. RESULTS:We demonstrated that the three mutant PA-PLA1α (p.W108R, p.H205R, and p.V437Gfs*4) were not secreted from the cells and induced more severe endoplasmic reticulum stress. We further showed that only the C-terminal variant p.V437Gfs*4 exhibited a significantly reduced binding affinity to C3orf52, consistent with the finding that PA-PLA1α and C3orf52 interacted via their C-termini. In addition, we confirmed that C3orf52 anchored PA-PLA1α on the plasma membrane in cultured cells. Finally, we showed that secretion of the downstream effector TGF-α via the LPA receptor LPA6 was markedly decreased in cells expressing each of the mutant PA-PLA1α proteins tested. CONCLUSION:Our results indicate that LIPH gene variants cause ARWH through multiple pathogenic pathways, while also providing new insight into the role of C3orf52 in hair follicle development in humans.
Background Extramammary Paget’s disease (EMPD) is a rare skin cancer whose etiology and pathogenesis remain unclear. Because of limited treatment options, patients with advanced stages have a poor prognosis; therefore, identifying novel biomarkers for early detection and evaluation of therapeutic efficacy is necessary. Objective To investigate the association between anterior gradient 2 (AGR2) expression and clinical features in patients with EMPD and the potential involvement of AGR2 in the pathogenesis of EMPD. Methods Sixty-two tissue samples and 60 serum samples were evaluated using immunohistochemistry and enzyme-linked immunosorbent assay. In vitro experiments were performed using the EMPD cell line, KS-EMPD-1, to assess the effects of silencing AGR2 on cell growth, invasion, and migration. Results Patients with AGR2 overexpression in tumor tissues tended to have a poor prognosis; however, the difference was not statistically significant. Serum AGR2 concentrations were significantly higher in patients with EMPD with or without metastasis than in healthy controls and decreased after treatment. AGR2 knockdown decreased cell number and induced apoptosis in EMPD cells, suggesting that AGR2 may influence the viability of EMPD cells via apoptosis. Conclusion AGR2 is overexpressed in patients with EMPD and plays an important role in the pathogenesis of EMPD.
Psoriasis is an inflammatory skin disease, which is distinguished by parakeratosis and hyperkeratosis. Abnormal keratinocyte activity is crucial to its onset and development. Recent evidence reveals the significance of metabolic reprogramming in keratinocytes during psoriasis progress, demonstrating its strong association with the control of immune and inflammatory responses in the cutaneous microenvironment. This review systematically outlines metabolic abnormalities in keratinocytes, emphasizing key metabolic targets in glucose, lipid, and amino acid metabolism that mediate psoriasis progression and discusses the application prospects of metabolic targets in clinical practice. The objective is to provide a rationale for developing novel psoriasis therapies based on the metabolic regulation of keratinocytes.
Autophagy, a highly conserved cellular degradation process, is essential for maintaining cellular homeostasis and responding to stress. Recent studies have highlighted the importance of autophagy in regulating epidermal functions, including keratinocyte differentiation and proliferation, epidermal lipid synthesis, inflammation, and antioxidation. In the epidermis, autophagy facilitates the removal of damaged organelles and protein aggregates, ensuring proper keratinocyte maturation and stratum corneum formation. Dysregulation of autophagy has been linked to various dermatological conditions, such as psoriasis, atopic dermatitis, and skin aging. Furthermore, autophagy modulates the inflammatory response in the skin by regulating cytokine production and immune cell activity. This review summarizes evidence supporting the role of autophagy in epidermal function and emphasizes its potential as a therapeutic target. Additionally, approaches to enhance autophagy are discussed.
BACKGROUND:Human skin includes an elastic fiber system consisting of oxytalan, elaunin, and elastin fibers, which are classified based on their fibrillin microfibril and elastin contents. These fibers decrease or lose their function with aging and photoaging. A disintegrin-like and metalloprotease domain with thrombospondin type I motifs-like 6 (ADAMTSL6) is a fibrillin microfibril-associated component that promotes fibrillin microfibril formation. OBJECTIVE:To investigate the contribution of ADAMTSL6 to the maintenance and aging/photoaging of dermal elastic fibers in human skin. METHODS:ADAMTSL6, fibrillin-1, and elastin in papillary dermis of sun-protected buttock skin and sun-exposed eyelid skin were detected by immunohistochemistry, and the contribution of ADAMTSL6 to elastic fiber formation in dermal fibroblasts was investigated. RESULTS:ADAMTSL6 colocalized with fibrillin-1 in oxytalan fibers and parts of elaunin fibers in the papillary dermis, but not in the reticular dermis, even when fibrillin-1 was present in the reticular dermis. Furthermore, ADAMTSL6 expression levels in eyelid skin decreased more markedly than in buttock skin with aging. Temporary knockdown of ADAMTSL6 expression by small interfering RNA in cultured dermal fibroblasts resulted in decreased expression of fibrillin-1, while stable knockdown of ADAMTSL6 by short hairpin RNA did not affect the deposition of fibrillin-1 but increased the expression and deposition of elastin in dermal fibroblast-derived matrix. CONCLUSION:Our results suggest that ADAMTSL6 contributes to the maintenance of oxytalan and elaunin fibers in the papillary dermis, and decreases slightly with intrinsic aging, but more prominently with photoaging. Maintaining ADAMTSL6 expression may contribute to preservation of dermal elastic fiber architecture.
BACKGROUND:In our previous studies, N,N-dimethylglycine sodium salt (DMG-Na) was found to exert anti-inflammatory and anti-oxidant effects in human epidermal keratinocytes and promote the synthesis of regenerating growth factors (e.g., vascular endothelial growth factor). OBJECTIVE:In the current investigation, we assessed the effects of DMG-Na to modulate hair follicle-derived dermal papilla (DP) senescence induced by oxidative (H2O2) or non-oxidative (Bromodeoxyuridine) stimuli using in vitro cultured human DP cells. Further, in two randomized, double-blind, placebo-controlled, parallel-group, sex-stratified in vivo studies, we determined the efficacy of a topical DMG-Na containing formulation on more than three hundred patients with hair loss. METHODS:In the in vitro arm, intracellular Ca2+ measurements, senescence-associated β-galactosidase determinations, qRT-PCR assays, and various immunolabeling methods were employed whereas multiple hair loss parameters were assessed in the in vivo human studies. RESULTS:DMG-Na (0.05%) significantly prevented the effects of H2O2 and Bromodeoxyuridine to upregulate the number of SA-β-Gal positive cells. Likewise, DMG-Na significantly normalized the expressions of several upregulated (e.g., matrix metalloproteinases 1 and 3, p21, interleukin-1β, tumor necrosis factor-α) or downregulated (e.g., Ki67, lamin B1, collagens 1A1 and 3A1) senescence-associated markers by the inducers. In line with these anti-senescence effects, in the human trials, topical formulations containing 0.5% DMG-Na significantly improved hair loss parameters. CONCLUSION:Our findings - together with our prior evidence that topically applied DMG-Na enhanced skin blood flow in humans - collectively suggest that DMG-Na is an effective and promising active for the management of hair conditions characterized by impaired cellular growth, repair, and dysregulated oxidative metabolic status.
Background Extramammary Paget’s disease is a rare cutaneous adenocarcinoma characterized by mucin-rich Paget cells and chronic inflammation, yet its molecular basis remains unclear. Objective To systematically characterize the proteomic and metabolomic landscape of EMPD, uncover immune heterogeneity, and identify molecular pathways underlying tumor progression and microenvironment remodeling. Methods We performed integrated proteomic and metabolomic analyses on 92 male tumor patients and 30 healthy controls, identifying 10,217 proteins and 1466 metabolites. Results Extramammary Paget’s disease lesions exhibited broad activation of inflammatory pathways. Immune profiling further uncovered substantial inflammatory heterogeneity, delineating immune-cold and immune-hot subtypes, with the latter associated with stronger invasive potential. Aberrant mucin-type glycosylation was also prominent, featuring Tn-modified MUC1 and MUC5AC accompanied by elevated GALNT7, GALNT6, GALNT4, and ST6GAL1, which correlated with inflammatory intensity. Metabolomic data demonstrated elevated levels of testosterone, dehydroepiandrosterone, and related intermediates in tumor tissues, indicating an androgen-enriched metabolic profile in extramammary Paget’s disease. Conclusion These findings reveal immune, glycoproteomic, and metabolomic pathways in extramammary Paget’s disease pathogenesis and provide novel insights for molecular classification and therapeutic targeting.
BACKGROUND:Pruritus is a major unpleasant sensation due to skin inflammation (inflammatory pruritus, IP), or due to a neurological disturbance despite the absence of objective symptoms of inflammation (non-inflammatory pruritus, NIP). It remains unknown whether a zinc deficiency (ZD) is related to pruritus. OBJECTIVE:To explore whether patients with IP or NIP showed alterations of serum zinc levels and evaluate the role of zinc in pruritus using an animal model. METHODS:Serum levels of zinc were compared between IP, NIP and non-pruritic controls. Patients with ZD were supplemented with oral zinc. Pruritus was evaluated using a numerical rating scale. Mice were treated with the mu opioid agonist morphine to induce NIP. Nalfurafine, a kappa opioid receptor agonist, was administrated prior to morphine treatment. RESULTS:Serum zinc levels were decreased in pruritic patients compared to non-pruritic controls and were significantly lower in NIP than IP patients. All NIP patients showed a ZD, and their itch symptoms were drastically resolved by zinc supplementation, along with normalization of zinc levels. ZD mice had a significantly higher sensitivity to morphine, compared to control mice. Treatment with nalfurafine ameliorated the morphine-induced pruritus in ZD mice. CONCLUSION:Our data strongly suggest that a ZD is an independent cause of NIP, which could be resolved by zinc supplementation. In addition, mouse model revealed that zinc plays a critical role in modification of opioid receptor-mediated signaling. This study reveals for the first time that zinc is crucially related to pruritus via opioid receptors.
Collagen XVIIα1, encoded by COL17A1 and historically known as BP180/BPAG2, is a type II transmembrane collagen enriched in hemidesmosomes of basal keratinocytes. Through interactions with integrin α6β4, laminin-332 and other dermal-epidermal junction (DEJ) components, collagen XVIIα1 links the keratin cytoskeleton to the basement membrane. Recent studies indicate that this junctional anchorage supports epidermal homeostasis by preserving stem cell adhesion, polarity and regenerative capacity. During aging, collagen XVIIα1 levels decline and proteolytic processing increases, including ADAM9/ADAM10-dependent ectodomain shedding and cleavage by inflammatory proteases. These changes weaken DEJ integrity and are associated with photoaging and impaired repair. In hair follicles, collagen XVIIα1 is also required for hair follicle stem cell (HFSC) maintenance, and its reduction is linked to HFSC exhaustion, hair aging phenotypes and altered niche signals that may influence melanocyte stem cell-dependent pigmentation. This review summarizes translational approaches targeting collagen XVIIα1 and proposes practical in vivo readouts for target engagement. Key gaps include mechanism attribution, durable functional restoration at the DEJ, persistence within the epidermal-follicular niche and a shortage of rigorous human studies.
Background The impact of psychological stress on vitiligo progression remains poorly understood. Objective We investigated the effects of substance P (SP) and its proteolytic fragments (SP1-9 and SP1-7) on mast cell activation and vitiligo exacerbation. Methods Skin specimens were biopsied from patients with active vitiligo, or from mice subjected to chronic restraint stress (CRS). A tyrosinase-related protein (Tyrp)-2180-188 peptide-induced vitiligo model was established in wild-type (WT) and in Mas-related G protein-coupled receptor-B2 (MrgprB2, MRGPRX2 in humans) knockout mice. Cultured keratinocytes (KCs), fibroblasts (FBs), and SH-SY5Y sensory neuronal-like cells were used in this study. The SP+ protein gene product 9.5 (PGP9.5)+ sensory innervation and the mast cell and CD8+ T cell counts were measured via dual immunofluorescence staining. Protein levels of matrix metalloproteinase (MMP)-9 and neprilysin in skin tissue homogenates from vitiligo patients or from CRS-treated vitiligo mice were measured by western blotting. In vitro proteolysis of SP was profiled by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and mast cell activation was assessed via flow cytometry. Results Increased SP+PGP9.5+ innervation and mast cells were observed in active vitiligo lesions and CRS-treated mouse skin. Intradermal injection of full-length SP and SP1-9, but not SP1-7, activated mast cells and worsened depigmentation. MrgprB2-/- mice showed reduced melanocyte loss and CD8+ T cell infiltration versus WT. MRGPRX2-silenced mast cells failed to produce IFNγ upon SP stimulation. LC-MS/MS revealed that KCs-derived MMP9, but not FBs-derived neprilysin, preferentially generated the pro-inflammatory SP1-9 fragment. Conclusion The SP-MRGPRX2 signaling axis represents a critical link between psychological stress and vitiligo progression.
Background Tissue resident memory (TRM) cells are of interest in chronic inflammatory skin diseases as they are believed to facilitate flares in the same anatomical area. IL-15 is an essential growth factor for the survival of TRM in the skin compartment. A main source of IL-15 are tissue-resident cells. Objective The purpose of this study was to explore the role of IL-15 in the chronification process of atopic dermatitis (AD). Methods Primary human keratinocytes and fibroblasts were cultured and exposed to a range of stimuli in order to assess their IL-15 expression and production, which were measured by qPCR and ELISA, respectively. RNAseq and PCR were performed from lesional and non-lesional atopic dermatitis (AD) biopsies. Results We tested a range of type I and type II response-associated cytokines and PAMPs on primary human fibroblasts and keratinocytes. The main inducer for IL-15 in keratinocytes proved to be IFNγ, while fibroblasts showed responsiveness to long-term exposure to IL-4. Transcriptomic analyses of AD skin biopsies confirmed that IL-15 was associated with a higher IFN signature and longer disease duration, and a significant correlation was observed between IL-15 and the TRM molecules CCR8 and CD69. Conclusion The epidermal compartment responds to IFNs with IL-15 expression. Analysis of patient-derived skin biopsies highlights higher expression of IL-15 in the context of a Th1 shift known to occur in chronic AD. These data suggest that flares require prompt intervention to avoid consolidation of an IFNγ-driven tissue memory.
