Artificial intelligence (AI) systems are increasingly being developed for dermatology, but the conditions under which patients trust these tools remain poorly characterized. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses-guided systematic narrative review synthesizes peer-reviewed empirical studies, published from January 1, 2015 through July 7, 2026, that directly assessed patient or public attitudes toward AI in dermatologic diagnosis, skin-cancer screening, image sharing, teledermatology image-quality support, and related patient-facing workflows. Eligible evidence included qualitative interviews and focus groups, surveys, preference/conjoint or vignette experiments, and early clinical deployments. Twenty studies met the inclusion criteria using the review framework. Across study designs, patients expressed conditional support for dermatology AI but consistently favored dermatologist-supervised AI over autonomous AI, especially for high-stakes diagnostic decisions. Trust was strengthened by visible clinician accountability, clear explanations of AI outputs and uncertainty, privacy safeguards, transparent data use, and evidence that performance is reliable across skin tone and diagnosis. Trust declined when AI was framed as replacing clinicians, when image governance was unclear, or when unequal performance was perceived. These findings support a model of augmented intelligence: dermatology AI should serve the clinical relationship; be subject to human oversight; and be evaluated and reported stratified by skin tone, diagnosis, and care context.

Phototherapy has been a cornerstone of psoriasis management since before the biologic era, and despite being eclipsed by systemic agents, it retains meaningful clinical utility. Narrowband ultraviolet B (NB-UVB) achieves clinically significant clearance rates, has been associated with greater improvement in overall health-related quality of life compared to adalimumab, and is effective across all skin tones. NB-UVB is associated with spatially distinct transcriptomic changes within plaques and downregulation of HLA-C-mediated antigen presentation on melanocytes. Home-based phototherapy, assessed in the LITE trial, performs non-inferiorly to office-based UV and is an accessible alternative. Coverage for home phototherapy is improving. Access barriers, insurance structure, and limited familiarity by prescribers remain obstacles to wider adoption. Addressing these through policy reform, expanded phototherapy coverage, and implementation science may represent an actionable path forward.

Keloids are refractory fibroproliferative disorders driven by dysregulated fibrosis and chronic inflammation. Current research has largely focused on the TGF-β signaling pathway and fibroblasts-the classical drivers of keloid formation-yet clinical outcomes remain unsatisfactory. To address this, we shifted our research focus to the immunometabolic axis, with particular emphasis on the regulatory role of IL4I1 (an amino acid oxidase) as an immunometabolic checkpoint. Our results demonstrated that IL4I1 was significantly upregulated in keloid tissues, accompanied by activation of its mediated tryptophan-kynurenine metabolic pathway and increased downstream lipid peroxidation products. In vivo knockout of Il4i1 suppressed collagen deposition in a skin fibrosis model, confirming that IL4I1 plays a critical facilitatory role in fibrotic progression. We performed drug screening and identified L-carnosine as an inhibitor of IL4I1. L-carnosine inhibits the enzymatic activity and protein stability of IL4I1, and exhibits prominent therapeutic efficacy in a keloid nude-mouse xenograft model. Through its enzymatic activity, IL4I1 mediates dendritic-cell-driven immunometabolic reprogramming and the formation of an immunosuppressive microenvironment, consequently accelerating fibrotic progression. This study highlights IL4I1 as a therapeutic target, and its small-molecule inhibitor L-carnosine holds promise to be translated into a safe and clinically attractive therapeutic modality.

The sympathetic nervous system regulates skin homeostasis by controlling thermoregulation, piloerection, vascular tone, epithelial stem cell activity, and immune surveillance. Although sympathetic nerves remodel during aging and inflammatory skin disease, the anatomical organization of cutaneous sympathetic circuits remains poorly defined. Here, we established a skin-specific retrograde viral tracing approach to define the anatomical organization of cutaneous sympathetic innervation. Dual-color retrograde tracing revealed that cutaneous sympathetic innervation is strictly ipsilateral and organized into broad, overlapping territories rather than discrete segmental domains. Anterior dorsal skin received input from multiple thoracic ganglia, whereas posterior dorsal skin exhibited greater inter-animal variability. Unexpectedly, the stellate ganglion consistently contributed to anterior dorsal skin innervation and, in a substantial subset of mice, also innervated posterior dorsal skin despite the absence of continuous labeling of intervening thoracic ganglia. Dual-tracer experiments demonstrated that individual stellate ganglion neurons can innervate both anterior and posterior dorsal skin, revealing unexpectedly long-range cutaneous projections. These findings establish an anatomical framework for cutaneous sympathetic organization, reveal overlapping ganglionic territories, and identify the stellate ganglion as a previously unrecognized source of sympathetic input to anterior and posterior dorsal skin, providing a foundation for investigating sympathetic remodeling during aging and skin disease.

Cutaneous squamous cell carcinoma (CSCC) is the most common metastatic skin cancer, with poor prognosis of metastatic disease. We investigated the role of the complement axis C3a/C3aR1 in CSCC progression. C3aR1 mRNA levels were elevated in CSCC tumors in vivo compared with normal skin. Single-cell RNA sequencing revealed C3aR1 expression in macrophages within CSCCs. In 3D spheroid co-cultures of CSCC cells, fibroblasts, and macrophages, RNA sequencing showed increased C3aR1 mRNA expression in the presence of M2-like macrophages. Immunofluorescence staining localized C3aR1-expressing cells predominantly at the peripheral region of spheroids. Recombinant C3a enhanced CSCC cell invasion, whereas C3aR1 inhibitor SB290157 inhibited their invasion in co-culture with fibroblasts and macrophages. Immunohistochemistry of normal skin, actinic keratoses, CSCC in situ, CSCC, and metastases demonstrated C3aR1 expression on tumor cells in a subset of metastatic CSCCs and metastases. All C3aR1-positive primary tumors were high-risk (Clark level V; AJCC stage III-IV). Multiplexed immunofluorescence showed that increase in C3aR1-positive tumor cells, M2-like macrophages, and cancer-associated fibroblasts in CSCC was associated with metastasis risk and poor disease-specific survival. These findings support a role for C3a/C3aR1 signaling in CSCC invasion and metastasis and identify C3aR1 as a potential therapeutic target in advanced disease.

RIPK4, IKKα and IRF6 are important regulators of epidermal development and homeostasis. The phenotypes of mice or men carrying inactivating variants show similar and overlapping defects in epidermal development, however, whether they act in a linear or parallel signaling pathway remains poorly understood. We show that in cultured normal human primary keratinocytes RIPK4 as well as IKKα and IRF6 control the expression of a genetic program responsible for formation of the cornified envelope, tight junctions and the lipid barrier. Both IKKα and RIPK4 can lead to IRF6 phosphorylation and activate IRF6 reporter activity in a kinase-dependent manner and RIPK4-induced IRF6 reporter activation is impaired in an IKKα-deficient background. We found that the RIPK4 kinase domain and its kinase activity are important for the interaction with IKKα and IRF6. In keratinocytes, IKKα and IRF6 regulate RIPK4-induced cytoskeletal rearrangements and expression of tight junction proteins such as Occludin and Claudin-4. Taken together, our data indicate that RIPK4 can engage IKKα to activate the IRF6 transcription factor to switch on keratinocyte differentiation.

Epigenetic dysregulation is implicated in inflammatory skin diseases such as rosacea, but its specific mechanisms in epidermal innate immunity remain unclear. Isotretinoin is an effective therapy for rosacea, yet its epigenetic mechanism of action is incompletely understood. This study analyzed human rosacea transcriptomic data, established an epidermis-specific Tet2 knockout (TET2eKO) mouse model, and knocked down TET2 in keratinocytes. TET2 and its catalytic product 5hmC were significantly downregulated in human rosacea lesions and in an LL-37-induced rosacea-like mouse model. TET2eKO mice exhibited exacerbated LL-37-induced erythema, telangiectasia, dermal thickening, and immune cell infiltration. Transcriptomic and functional analyses coupled with hMeDIP-qPCR demonstrated that TET2 deficiency led to excessive activation of the JAK2/STAT3 pathway through loss of direct epigenetic constraint, driving the upregulation of pro-inflammatory cytokines and chemokines in keratinocytes. Isotretinoin treatment restored TET2/5hmC levels, suppressed JAK2/STAT3 activation, and mitigated inflammatory responses both in vitro and in vivo. These results indicate that TET2 functions as a key epigenetic brake on cutaneous inflammation by negatively regulating the JAK2/STAT3 pathway in keratinocytes. Consequently, the therapeutic effect of isotretinoin is closely associated with the restoration of TET2 function, providing mechanistic insight into the management of inflammatory dermatoses.

Pemphigoid diseases (PD) are autoimmune blistering disorders in which alterations of the skin and gut microbiota have been reported, yet how microbial variation relates to disease severity remains unclear. Using a bullous pemphigoid-like mouse model, we compared genetically identical C57BL/6J mice from two breeding facilities that differed in their baseline microbiota. Mice from Charles River developed markedly milder disease than in-house-bred animals. Co-housing partially homogenized their gut microbiota, shifting in-house mice asymmetrically toward the Charles River community, coinciding with reduced disease severity in co-housed in-house mice. The skin microbiota showed more modest and less consistent shifts, potentially reflecting its lower biomass and higher technical noise. Lower gut microbial diversity and enrichment of pro-inflammatory taxa like Turicimonas muris and Muribaculum intestinale were linked to more severe disease, whereas taxa such as Lactobacillus intestinalis and Parabacteroides distasonis correlated with protection. A gut taxon belonging to Scatocola was identified as a candidate negative predictor of disease severity in correlation and machine-learning analyses. Together, these findings support an association between natural variation in the gut microbiota and autoimmune skin inflammation and identify candidate microbial taxa that warrant further functional validation.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent painful abscesses and tunnels in flexural sites. The mechanisms driving HS pathogenesis, particularly the interactions between epithelial, stromal and immune cell populations, remain incompletely understood. To characterise the cellular and molecular landscape of HS, we analysed lesional skin from severe HS patients using single-cell RNA-sequencing and spatial transcriptomics, with a focus on fibroblast-keratinocyte interactions. We identified a migratory S100+ pathogenic keratinocyte state enriched within HS lesions and observed spatially distinct fibroblast populations associated with different tissue compartments. COL6A5+ papillary fibroblasts showed spatial association with undifferentiated keratinocyte populations and predicted fibroblast-keratinocyte communication networks, whereas APOD+ fibroblasts were associated with immune-rich regions containing activated B cells and plasma cells, consistent with TLO-like immune aggregates. Ligand-receptor inference and spatial analyses predicted extensive fibroblast-keratinocyte and fibroblast-immune interactions within HS lesions. These findings support a model in which severe HS contains distinct epithelial and inflammatory stromal niches that may contribute to disease persistence. More broadly, they provide a framework for understanding how epithelial, stromal and immune compartments interact within HS lesions and may help explain the limited efficacy of therapies targeting individual inflammatory pathways in the treatment of HS.

Skin aging is driven by intrinsic and extrinsic factors that promote fibroblast senescence and dermal extracellular matrix degradation. Melatonin has potent antioxidant and anti-inflammatory activities. Here, we investigated the anti-aging effects of melatonin in human dermal fibroblasts and aged mouse skin, focusing on the pro-inflammatory chemokine CXCL9. Replicative-, irradiation-, and doxorubicin-induced senescence models of human dermal fibroblasts were used to assess the effects of melatonin. Melatonin significantly reduced the proportion of senescence-associated β-galactosidase-positive cells (38.5%-41.6%) and suppressed the expression of senescence markers, such as p16[INK4a] and γH2AX, and the senescence-associated secretory phenotype (SASP) factors IL1A and IL6. Additionally, melatonin lowered intracellular reactive oxygen species levels (50.8%-87.7%), restored mitochondrial membrane potential, ATP levels, and reduced STAT1 phosphorylation. CXCL9 was markedly upregulated in senescent fibroblasts and was suppressed by melatonin treatment. siRNA-mediated CXCL9 knockdown mimicked the anti-senescence effects of melatonin, whereas the melatonin receptor antagonist luzindole attenuated these effects. Furthermore, melatonin pretreatment protected young fibroblasts against irradiation-induced senescence. In vivo, intradermal melatonin administration increased dermal thickness by 97% and collagen density by 23%, while reducing SASP factor expression. Collectively, these findings suggest that melatonin attenuates dermal fibroblast senescence in association with reduced CXCL9 expression and preservation of mitochondrial homeostasis.

Mast cells (MCs) are key regulators of cutaneous immune responses and play a central role in allergic and non-IgE-mediated skin inflammation by activating the Mas-related G protein-coupled receptor X2 (MRGPRX2). The inhibitory receptor CD300f has been shown to modulate MC activation, but its role in regulating MRGPRX2-dependent signaling remains unclear. Here, we investigated CD300f expression and function in human skin MCs and its impact on MRGPRX2-mediated responses, with some comparison to IgE-mediated responses. CD300f was expressed on human skin MCs, and its surface expression increased following MRGPRX2 activation. Engagement of CD300f significantly attenuated MC activation induced by MRGPRX2-dependent stimuli, including substance P, vancomycin, and quinolone drugs. Transcriptomic analyses in CD300f-LAD2 revealed that CD300f signaling suppressed activation-associated gene programs after substance P stimulation, including NF-κB and MAPK pathways. Notably, CD300f engagement markedly downregulated microphthalmia-associated transcription factor (MITF), as confirmed at the protein level in LAD2 and skin MCs. MITF inhibition with TT012 and CD300f triggering enhance inhibitory responses, decreasing MITF and MITF-target expression more strongly. Conversely, lysyl-tRNA synthetase overexpression increases MITF expression and significantly reduces CD300f-mediated inhibition of both MRGPRX2- and FcεRI-dependent signaling. These findings reveal a CD300f-MITF regulatory axis that limits skin MC activation and inflammatory responses.

Repeated injury can impair transitions between cellular phenotypes, potentially leading to pathological tissue repair. In recessive dystrophic epidermolysis bullosa (RDEB), collagen VII deficiency predisposes to repeated tissue injury, driving inflammation and fibrosis. Although fibroblasts are major effector cells in RDEB fibrosis, their phenotypic and molecular changes underlying disease progression remain elusive. Through cellular and in situ analyses of clinical samples and tissue from an RDEB mouse model, we disclose a phenotypic switch in dermal fibroblasts during disease progression. At early stages, fibroblasts display a contractile phenotype, whereas at later stages they transition toward a less contractile phenotype with increased production of a fibrosis-promoting extracellular matrix, indicated by high tenascin-C levels. Dysregulated epidermal growth factor receptor (EGFR) signaling through AKT appears central to this switch. At early stages, EGFR signaling and AKT support fibroblast contractility, whereas at later stages this signaling becomes intrinsically blunted, with ADAM17 implicated in the transition. The type of inflammation modulates this phenotypic switch. Thus, RDEB fibroblasts transition from a contractile to a less contractile but pro-fibrotic phenotype during disease progression. These findings suggest that reducing cellular contractility may be advantageous at earlier disease stages, whereas extracellular matrix-targeting strategies may have higher priority at later stages.