Biosignatures of defective sebaceous gland activity in sebum-rich and sebum-poor skin areas in adult atopic dermatitis.

Atopic dermatitis (AD) is a composite disease presenting disruption of the skin permeability barrier (SPB) in the stratum corneum (SC). Recent evidence supports derangement of the sebaceous gland (SG) activity in the AD pathomechanisms. The objective of this study was to delineate profiles of both sebaceous and epidermal lipids and of aminoacids from SG-rich (SGR) and SG-poor (SGP) areas in AD. Both sebum and SC were sampled from SGR areas, while SC was sampled also from SGP areas in 54 adult patients with AD, consisting of 34 and 20 subjects, respectively with and without clinical involvement of face, and in 44 age and sex-matched controls. Skin biophysics were assessed in all sampling sites. Disruption of the SBP was found to be associated with dysregulated lipidome. Abundance of sapienate and lignocerate, representing, respectively, sebum and the SC type lipids, were decreased in sebum and SC from both SGR and SGP areas. Analogously, squalene was significantly diminished in AD, regardless the site. Extent of lipid derangement in SGR areas was correlated with the AD severity. The abundance of aminoacids in the SC from SGR areas was altered more than that determined in SGP areas. Several gender-related differences were found in both controls and AD subgroups. In conclusion, the SG activity was differently compromised in adult females and males with AD, in both SGR and SGP areas. In AD, alterations in the aminoacidome profiles were apparent in the SGR areas. Lipid signatures in association with aminoacidome and skin physical properties may serve the definition of phenotype clusters that associate with AD severity and gender.

Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial.

BACKGROUND: Vitiligo is a chronic autoimmune disorder characterized by depigmented patches of the skin. OBJECTIVE: To evaluate the efficacy and safety of ritlecitinib, an oral JAK3 (Janus kinase)/TEC (tyrosine kinase expressed in hepatocelluar carcinoma) inhibitor, in patients with active nonsegmental vitiligo in a phase 2b trial (NCT03715829). METHODS: Patients were randomized to once-daily oral ritlecitinib ± 4-week loading dose (200/50 mg, 100/50 mg, 30 mg, or 10 mg) or placebo for 24 weeks (dose-ranging period). Patients subsequently received ritlecitinib 200/50 mg daily in a 24-week extension period. The primary efficacy endpoint was percent change from baseline in Facial-Vitiligo Area Scoring Index at week 24. RESULTS: A total of 364 patients were treated in the dose-ranging period. Significant differences from placebo in percent change from baseline in Facial-Vitiligo Area Scoring Index were observed for the ritlecitinib 50 mg groups with (-21.2 vs 2.1; P < .001) or without (-18.5 vs 2.1; P < .001) a loading dose and ritlecitinib 30 mg group (-14.6 vs 2.1; P = .01). Accelerated improvement was observed after treatment with ritlecitinib 200/50 mg in the extension period (n = 187). No dose-dependent trends in treatment-emergent or serious adverse events were observed across the 48-week treatment. LIMITATIONS: Patients with stable vitiligo only were excluded. CONCLUSIONS: Oral ritlecitinib was effective and well tolerated over 48 weeks in patients with active nonsegmental vitiligo.

Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the international Vitiligo Task Force-Part 2: Specific treatment recommendations.

BACKGROUND: The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking. OBJECTIVES: To develop internationally agreed-upon expert-based recommendations for the treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak-inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB-UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed. CONCLUSIONS: This international consensus statement culminated in expert-based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs.

Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the International Vitiligo Task Force Part 1: towards a new management algorithm.

BACKGROUND: The treatment of vitiligo can be challenging and depends on several factors such as the subtype, disease activity, vitiligo extent, and treatment goals. Vitiligo usually requires a long-term approach. To improve the management of vitiligo worldwide, a clear and up-to-date guide based on international consensus with uniform stepwise recommendations is needed. OBJECTIVES: To reach an international consensus on the nomenclature and to develop a management algorithm for the diagnosis, assessment, and treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence of topics included in the algorithms. A survey was utilized to resolve remaining issues among a core group of eight experts. Subsequently, the unanimous recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The algorithms highlight the importance of shared decision-making. Dermatologists are encouraged to provide patients with detailed explanations of the prognosis and expected therapeutic outcomes based on clinical examination. The treatment goal should be discussed and clearly emphasized to patients given the different approaches for disease stabilization and repigmentation. The evaluation of disease activity remains a cornerstone in the tailor-made approach to vitiligo patients. CONCLUSIONS: These new treatment algorithms are intended to guide clinical decision-making in clinical practice. Promising novel therapies for vitiligo are on the horizon, further highlighting the need for reliable outcome measurement instruments and greater emphasis on shared decision-making.

Skin Anti-Inflammatory Potential with Reduced Side Effects of Novel Glucocorticoid Receptor Agonists.

Glucocorticoids (GCs) are commonly used in the treatment of inflammatory skin diseases, although the balance between therapeutic benefits and side effects is still crucial in clinical practice. One of the major and well-known adverse effects of topical GCs is cutaneous atrophy, which seems to be related to the activation of the glucorticoid receptor (GR) genomic pathway. Dissociating anti-inflammatory activity from atrophogenicity represents an important goal to achieve, in order to avoid side effects on keratinocytes and fibroblasts, known target cells of GC action. To this end, we evaluated the biological activity and safety profile of two novel chemical compounds, DE.303 and KL.202, developed as non-transcriptionally acting GR ligands. In primary keratinocytes, both compounds demonstrated anti-inflammatory properties inhibiting NF-κB activity, downregulating inflammatory cytokine release and interfering with pivotal signaling pathways involved in the inflammatory process. Of note, these beneficial actions were not associated with GC-related atrophic effects: treatments of primary keratinocytes and fibroblasts with DE.303 and KL.202 did not induce, contrarily to dexamethasone-a known potent GC-alterations in extracellular matrix components and lipid synthesis, thus confirming their safety profile. These data provide the basis for evaluating these compounds as effective alternatives to the currently used GCs in managing inflammatory skin diseases.

Therapeutic potential of adipose tissue-derivatives in modern dermatology.

Stem cell-mediated therapies in combination with biomaterial and growth factor-based approaches in regenerative medicine are rapidly evolving with increasing application beyond the dermatologic field. Adipose-derived stem cells (ADSCs) are the more frequently used adult stem cells due to their abundance and easy access. In the case of volumetric defects, adipose tissue can take the shape of defects, restoring the volume and enhancing the regeneration of receiving tissue. When regenerative purposes prevail on volume restoration, the stromal vascular fraction (SVF) rich in staminal cells, purified mesenchymal stem cells (MSCs) or their cell-free derivatives grafting are favoured. The therapeutic efficacy of acellular approaches is explained by the fact that a significant part of the natural propensity of stem cells to repair damaged tissue is ascribable to their secretory activity that combines mitogenic factors, cytokines, chemokines and extracellular matrix components. Therefore, the secretome's ability to modulate multiple targets simultaneously demonstrated preclinical and clinical efficacy in reversing pathological mechanisms of complex conditions such atopic dermatitis (AD), vitiligo, psoriasis, acne and Lichen sclerosus (LS), non-resolving wounds and alopecia. This review analysing both in vivo and in vitro models gives an overview of the clinical relevance of adipose tissue-derivatives such as autologous fat graft, stromal vascular fraction, purified stem cells and secretome for skin disorders application. Finally, we highlighted the major disease-specific limitations and the future perspective in this field.

Efficacy and safety of N-acetyl-GED-0507-34-LEVO gel in patients with moderate-to severe facial acne vulgaris: a phase IIb randomized double-blind, vehicle-controlled trial.

BACKGROUND: Preliminary in vitro and in vivo studies have supported the efficacy of the peroxisome proliferator-activated receptor-γ (PPARγ) modulator N-acetyl-GED-0507-34-LEVO (NAC-GED) for the treatment of acne-inducing sebocyte differentiation, improving sebum composition and controlling the inflammatory process. OBJECTIVES: To evaluate the efficacy and safety of NAC-GED (5% and 2%) in patients with moderate-to-severe facial acne vulgaris. METHODS: This double-blind phase II randomized controlled clinical trial was conducted at 36 sites in Germany, Italy and Poland. Patients aged 12-30 years with facial acne, an Investigator Global Assessment (IGA) score of 3-4, and an inflammatory and noninflammatory lesion count of 20-100 were randomized to topical application of the study drug (2% or 5%) or placebo (vehicle), once daily for 12 weeks. The co-primary efficacy endpoints were percentage change from baseline in total lesion count (TLC) and IGA success at week 12; the safety endpoints were adverse events (AEs) and serious AEs. This study was registered with EudraCT (2018-003307-19). RESULTS: Between Q1 in 2019 and Q1 in 2020 450 patients [n = 418 (92·9%) IGA 3; n = 32 (7·1%) IGA 4] were randomly assigned to NAC-GED 5% (n = 150), NAC-GED 2% (n = 150) or vehicle (n = 150). The percentage change in TLC reduction was statistically significantly higher in both the NAC-GED 5% [-57·1%, 95% confidence interval (CI) -60·8 to -53·4; P < 0·001] and NAC-GED 2% (-44·7%, 95% CI -49·1 to -40·1; P < 0·001) groups compared with vehicle (-33·9%, 95% CI -37·6 to -30·2). A higher proportion of patients treated with NAC-GED 5% experienced IGA success (45%, 95% CI 38-53) vs. the vehicle group (24%, 95% CI 18-31; P < 0·001). The IGA success rate was 33% in the NAC-GED 2% group (P = not significant vs. vehicle). The percentage of patients who had one or more AEs was 19%, 16% and 19% in the NAC-GED 5%, NAC-GED 2% and vehicle groups, respectively. CONCLUSIONS: The topical application of NAC-GED 5% reduced TLC, increased the IGA success rate and was safe for use in patients with acne vulgaris. Thus, NAC-GED, a new PPARγ modulator, showed an effective clinical response. What is already known about this topic? Acne vulgaris, one of the most common dermatological diseases, affects more than 85% of adolescents. There is a medical need for innovative and safe treatment of acne vulgaris. The peroxisome proliferator-activated receptor-γ (PPARγ) is involved in lipid metabolism and specifically in cell differentiation, sebum production and the inflammatory reaction. What does this study add? N-acetyl-GED-0507-34-LEVO (NAC-GED 5%), a PPARγ modulator, significantly improves acne manifestations in patients with moderate-to-severe acne and is safe and well tolerated. The results suggest that the PPARγ receptor is a novel therapeutic target for acne. The results provide a basis for a large phase III trial to assess the effectiveness and safety profile of NAC-GED in combating a disease that afflicts 80-90% of adolescents.

Bovine colostrum induces the differentiation of human primary keratinocytes.

Bovine colostrum, the first milk secreted by the mammary glands of cows shortly after they have given birth, provides a natural source of bioactive substances helpful to promote tissue development and repair, and to maintain a healthy immune system. Owing to its properties, the use of colostrum in the treatment of human diseases is under investigation. We evaluated the biological activity of colostrum on human primary keratinocytes, focusing on its effects with regard to a proliferation/differentiation balance. Using cellular and molecular approaches, we showed that colostrum favors a cell cycle withdrawal by increasing the expression of p21/WAF1 and p27/KIP1. It also promotes the transition of keratinocytes from a proliferating to a differentiating state, as assessed by a decrease in keratin 5 and an increase in keratin 16. We demonstrated the ability of colostrum to induce the expression of early and late differentiation markers (keratin 1, involucrin, and filaggrin) and the synthesis of caspase 14 and bleomycin hydrolase, the two main enzymes involved in filaggrin maturation. Moreover, we showed that bovine colostrum is able to promote keratinocyte stratification and terminal differentiation not only in two-dimensional (2D), but also in a more physiological system of three-dimensional (3D) skin equivalents. Finally, we demonstrated that colostrum stimulates cell differentiation through the PI3K/PLC-γ1/PKCα pathways mainly associated to tyrosine kinase receptors. These results suggest the possibility to benefit from colostrum properties for the treatment of skin diseases characterized by altered differentiation and perturbed barrier function.

Metabolic Comorbidities in Vitiligo: A Brief Review and Report of New Data from a Single-Center Experience.

Among disorders of pigmentation, vitiligo is the most common, with an estimated prevalence between 0.5% and 1%. The disease has gathered increased attention in the most recent years, leading to a better understanding of the disease's pathophysiology and its implications and to the development of newer therapeutic strategies. A better, more integrated approach is already in use for other chronic inflammatory dermatological diseases such as psoriasis, for which metabolic comorbidities are well-established and part of the routine clinical evaluation. The pathogenesis of these might be linked to cytokines which also play a role in vitiligo pathogenesis, such as IL-1, IL-6, TNF-α, and possibly IL-17. Following the reports of intrinsic metabolic alterations reported by our group, in this brief review, we analyze the available data on metabolic comorbidities in vitiligo, accompanied by our single-center experience. Increased awareness of the metabolic aspects of vitiligo is crucial to improving patient care.

Profiling Cancer-Associated Fibroblasts in Melanoma.

Solid tumors are complex systems characterized by dynamic interactions between neoplastic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have pleiotropic functions in tumor growth and extracellular matrix remodeling implicated in local invasion and distant metastasis. CAFs additionally participate in the inflammatory response of the tumor site by releasing a variety of chemokines and cytokines. It is becoming clear that understanding the dynamic, mutual melanoma-fibroblast relationship would enable treatment options to be amplified. To better characterize melanoma-associated fibroblasts, here we analyzed low-passage primary CAFs derived from advanced-stage primary skin melanomas, focusing on the immuno-phenotype. Furthermore, we assessed the expression of several CAF markers and the production of growth factors. To deepen the study of CAF-melanoma cell crosstalk, we employed CAF-derived supernatants and trans-well co-culture systems to evaluate the influences of CAFs on (i) the motogenic ability of melanoma cells, (ii) the chemotherapy-induced cytotoxicity, and (iii) the release of mediators active in modulating tumor growth and spread.

Anti-Inflammatory and Pro-Differentiating Properties of the Aryl Hydrocarbon Receptor Ligands NPD-0614-13 and NPD-0614-24: Potential Therapeutic Benefits in Psoriasis.

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor expressed in all skin cell types, plays a key role in physiological and pathological processes. Several studies have shown that this receptor is involved in the prevention of inflammatory skin diseases, e.g., psoriasis, atopic dermatitis, representing a potential therapeutic target. We tested the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two new synthetic AhR ligands structurally related to the natural agonist FICZ, known to be effective in psoriasis. NPD-0614-13 and NPD-0614-24 did not alter per se the physiological functions of the different skin cell populations involved in the pathogenesis of inflammatory skin diseases. In human primary keratinocytes stimulated with tumor necrosis factor-α or lipopolysaccharide the compounds were able to counteract the altered proliferation and to dampen inflammatory signaling by reducing the activation of p38MAPK, c-Jun, NF-kBp65, and the release of cytokines. Furthermore, the molecules were tested for their beneficial effects in human epidermal and full-thickness reconstituted skin models of psoriasis. NPD-0614-13 and NPD-0614-24 recovered the psoriasis skin phenotype exerting pro-differentiating activity and reducing the expression of pro-inflammatory cytokines and antimicrobial peptides. These data provide a rationale for considering NPD-0614-13 and NPD-0614-24 in the management of psoriasis.

Standardizing serial photography for assessing and monitoring vitiligo: A core set of international recommendations for essential clinical and technical specifications.

BACKGROUND: Clinical photography is an important component of the initial assessment and follow-up of patients with vitiligo in clinical practice and research settings. Standardization of this photographic process is essential to achieve useful, high-quality, and comparable photographs over time. OBJECTIVE: The aim is to develop an international consensus for a core set of recommendations for standardized vitiligo clinical photography. METHODS: Based an international meeting of vitiligo experts, a standard operating procedure was developed for vitiligo photography in daily practice and research settings. This protocol was subsequently reviewed by 20 vitiligo experts until agreement was reached. RESULTS: The resulting protocol includes a set of 10 and 15 photographs for clinical practice and research purposes, respectively. The photographic series are based on anatomic units included in the Vitiligo Extent Score. Furthermore, graphic representations of standardized positioning and suggestions for guidelines to standardize the process (background color, lighting, position marking, scales, materials, instruments) for both color and ultraviolet photographs are described. CONCLUSIONS: This consensus-based protocol for vitiligo photography will harmonize imaging for both clinical practice, translational research, and clinical trials. It can improve outcome assessment, foster multicenter collaboration, and promote better communication with patients regarding outcomes of treatment.

Paired Basic Amino Acid-cleaving Enzyme 4 (PCSK6): An Emerging New Target Molecule in Human Melanoma.

Although recent therapeutic developments raise hope, melanoma remains a devastating disease with a need for new treatment targets. In other tumours prohormone convertases have been shown to be pro-tumourigenic as they are involved in processing preforms of matrix-metalloproteinases, growth factors and adhesion molecules. The aim of this study was to look for new treatment options for melanoma, by investigating the role of the prohormone convertase Paired basic Amino acid-Cleaving Enzyme 4 (PACE4/PCSK6) in melanoma cell lines and human melanoma tissue. PACE4-transfected A375 melanoma cells displayed significantly increased proliferation, MMP-2 production, gelatinase activity and migratory capacity in vitro compared with sham-transfected cells. In vivo, elevated PACE4 expression resulted in significantly increased tumour growth on immunodeficient mice. In the majority of 45 human primary melanomas and melanoma metastases ex vivo PACE4 immunoreactivity was detectable, while it was absent in in situ melanomas. These results indicate PACE4 as a regulator of melanoma cell aggressiveness.

The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview.

Nevoid basal cell carcinoma syndrome (NBCCS), also named Gorlin syndrome, is a rare multisystem genetic disorder characterized by marked predisposition to basal cell carcinomas (BCCs), childhood medulloblastomas, maxillary keratocysts, celebral calcifications, in addition to various skeletal and soft tissue developmental abnormalities. Mutations in the tumor suppressor gene PATCHED1 (PTCH1) have been found to be associated in the majority of NBCCS cases. PATCH1 somatic mutations and loss of heterozygosity are also very frequent in sporadic BCCs. Unlike non-syndromic patients, NBCCS patients develop multiple BCCs in sun-protected skin area starting from early adulthood. Recent studies suggest that dermo/epidermal interaction could be implicated in BCC predisposition. According to this idea, NBCCS fibroblasts, sharing with keratinocytes the same PTCH1 germline mutation and consequent constitutive activation of the Hh pathway, display features of carcinoma-associated fibroblasts (CAF). This phenotypic traits include the overexpression of growth factors, specific microRNAs profile, modification of extracellular matrix and basement membrane composition, increased cytokines and pro-angiogenic factors secretion, and a complex alteration of the Wnt/-catenin pathway. Here, we review studies about the involvement of dermal fibroblasts in BCC predisposition of Gorlin syndrome patients. Further, we matched the emerged NBCCS fibroblast profile to those of CAF to compare the impact of cell autonomous "pre-activated state" due to PTCH1 mutations to those of skin tumor stroma.

Extracellular fraction of adipose tissue as an innovative regenerative approach for vitiligo treatment.

Vitiligo is a common, disfiguring autoimmune disease that negatively affects patients' self-esteem and quality of life. Current treatments are moderately effective in reversing disease and promoting melanocyte regeneration. Thus, therapeutic advanced strategies are emerging from regenerative medicine. It has recently emerged that adipose tissue secretome may be used as a cell-free therapy in skin regeneration since paracrine functions of adipose-derived stem cells alone are responsible for most of the therapeutic effect of stem cells in several animal disease models. In this study, we tested the effect of adipose tissue extracellular fraction (AT-Ex) isolated from lipoaspirates on dermal and epidermal vitiligo cells in vitro. Using this experimental model, we demonstrated that molecules secreted by adipose tissue ameliorate the capability to counteract oxidative stress by a physiological stimulation of intracellular antioxidant enzymes and positively impact on cell proliferation. Due to the presence of Wnt-secreted factors, AT-Ex treatment promotes glycogen synthase kinase 3ß inactivation and consequently Wnt/ß-catenin pathway activation. Collectively, our findings show that AT-Ex could be useful as a natural approach to improve treatment of vitiligo.

Involvement of non-melanocytic skin cells in vitiligo.

Despite melanocytes are the key players in vitiligo, a continuous cross-talk between epidermal and dermal cells may strictly affect their functionality, in both lesional skin and non-lesional skin. Focusing on this interplay, we have reviewed existing literature supporting evidence on cellular and functional alterations of surrounding epidermal keratinocytes, extracellular matrix (ECM) proteins and fibroblasts in the underlying dermal compartment that may contribute to melanocyte disappearance in vitiligo. We have also examined some clinical and therapeutic aspects of the disease to sustain the non-exclusive involvement of melanocytes within vitiligo. As a result, a different and more complex scenario has appeared that may enable to provide better understanding about origins and progress of vitiligo and that should be considered in the evaluation of new treatment approaches.

Acquired disorders with hypopigmentation: A clinical approach to diagnosis and treatment.

Acquired hypopigmented skin changes are commonly encountered by dermatologists. Although hypopigmentation is often asymptomatic and benign, occasional serious and disabling conditions present with cutaneous hypopigmentation. A thorough history and physical examination, centered on disease distribution and morphologic findings, can aid in delineating the causes of acquired hypopigmented disorders. The second article in this 2-part continuing medical education series focuses on conditions with a hypopigmented phenotype. Early diagnosis and appropriate management of these disorders can improve a patient's quality of life, halt disease progression, and prevent irreversible disability.

Acquired disorders with depigmentation: A systematic approach to vitiliginoid conditions.

Acquired disorders with depigmentation are commonly encountered by dermatologists and present with a wide differential diagnosis. Vitiligo, the most common disorder of acquired depigmentation, is characterized by well-defined depigmented macules and patches. Other conditions, such as chemical leukoderma, can present with similar findings, and are often easily mistaken for vitiligo. Key clinical features can help differentiate between acquired disorders of depigmentation. The first article in this continuing medical education series focuses on conditions with a vitiligo-like phenotype. Early recognition and adequate treatment of these conditions is critical in providing appropriate prognostication and treatment.

Endogenous N-acyl taurines regulate skin wound healing.

The intracellular serine amidase, fatty acid amide hydrolase (FAAH), degrades a heterogeneous family of lipid-derived bioactive molecules that include amides of long-chain fatty acids with taurine [N-acyl-taurines (NATs)]. The physiological functions of the NATs are unknown. Here we show that genetic or pharmacological disruption of FAAH activity accelerates skin wound healing in mice and stimulates motogenesis of human keratinocytes and differentiation of human fibroblasts in primary cultures. Using untargeted and targeted lipidomics strategies, we identify two long-chain saturated NATs-N-tetracosanoyl-taurine [NAT(24:0)] and N-eicosanoyl-taurine [NAT(20:0)]-as primary substrates for FAAH in mouse skin, and show that the levels of these substances sharply decrease at the margins of a freshly inflicted wound to increase again as healing begins. Additionally, we demonstrate that local administration of synthetic NATs accelerates wound closure in mice and stimulates repair-associated responses in primary cultures of human keratinocytes and fibroblasts, through a mechanism that involves tyrosine phosphorylation of the epidermal growth factor receptor and an increase in intracellular calcium levels, under the permissive control of transient receptor potential vanilloid-1 receptors. The results point to FAAH-regulated NAT signaling as an unprecedented lipid-based mechanism of wound-healing control in mammalian skin, which might be targeted for chronic wound therapy.