Rosacea is a globally prevalent chronic inflammatory skin disorder that markedly impairs quality of life, yet treatment options are limited. A characteristic feature of rosacea is macrophage infiltration, whose role in disease pathogenesis remains incompletely understood beyond inflammation; here, we identify their contribution to fibrotic remodeling through macrophage-to-myofibroblast transition (MMT). Serum proteomics revealed that TGF-β1 was prominently elevated in rosacea patients. Moreover, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and histological staining of skin biopsies demonstrated that fibrotic remodeling was already evident at inflammation-dominant stages, with macrophages progressively acquiring myofibroblast-like features through MMT. These observations were recapitulated in LL37-induced mouse models by scRNA-seq and ST, further validated by lineage tracing using Cx3cr1-GFP knock-in mice. Interestingly, macrophage depletion markedly alleviated LL37-induced fibrotic remodeling, underscoring the pathogenic role of MMT. Through integrative screening, we subsequently identified Bruceine A (BA), a natural quassinoid that suppressed fibrotic remodeling by reducing MMT and attenuating keratinocyte-driven inflammation in vivo. BA directly targeted STAT3 and interfered with its palmitoylation-dependent activation, thereby disrupting profibrotic and inflammatory signaling. Our findings establish MMT as a driver of fibrotic remodeling in rosacea, define STAT3 palmitoylation as a therapeutic target, and position BA as a dual-acting candidate for mechanism-based intervention.

BACKGROUND:Ultraviolet (UV)-induced reactive oxygen species (ROS) production, DNA damage, and chronic inflammation lead to skin aging and cancers. Ginkgetin (GK), a biflavonoid derived from Ginkgo biloba, has known anti-inflammatory and antioxidant activities, but its anti-photoaging effect remains unclear. OBJECTIVE:This study aimed to determine whether GK could alleviate UV-induced photoaging by reducing oxidative stress and promoting DNA repair. METHODS:The efficacy of microneedle-assisted topical GK was evaluated in a UV-induced SKH-1 mouse model of photoaging using dermoscopy and histopathological analysis. We conducted transcriptomic profiling and network pharmacology to identify the underlying mechanism. In UV-irradiated human dermal fibroblasts (HDFs), cellular senescence markers were assessed by SA-β-gal staining and Western blotting. Intracellular ROS levels and mitochondrial membrane potential were measured using DCFH-DA and JC-1 staining, respectively. Apoptosis, cell cycle progression, and senescence-associated secretory phenotype (SASP)-related cytokine expression were analyzed by flow cytometry, Western blotting, RT-qPCR, and ELISA. DNA damage and repair in UV-irradiated HaCaT cells were evaluated by comet assay and γ-H2AX immunofluorescence. Homologous recombination repair (HRR)-related proteins and RAD51 foci formation were analyzed by Western blotting and confocal microscopy, respectively. Functional validation was performed using the AKT inhibitor MK2206 and the HRR inhibitor B02. RESULTS:GK significantly reduced wrinkle formation, epidermal hyperplasia, and collagen loss in UV-induced mice. It decreased ROS levels, restored mitochondrial potential, reduced senescence markers, suppressed SASP cytokines and MMP1/2 expression, promoted cell cycle progression, and inhibited apoptosis by regulating the BCL2/BAX ratio. Importantly, GK enhanced DNA repair by promoting HRR, as directly demonstrated by the upregulation of key HRR proteins (BRCA2, RAD51) and the acceleration of RAD51 foci formation. Critically, these DNA repair-enhancing effects were abolished by inhibition of either AKT or HRR, demonstrating that the AKT-HRR axis is indispensable for GK's repair-promoting function. CONCLUSION:GK may serve as a potential therapeutic candidate for UV-induced photoaging by virtue of its dual capacity to scavenge ROS and enhance AKT-mediated DNA repair.

Clinical evidence supports the anti-photoaging efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT), yet its mechanism remains elusive. Paradoxically, ALA-PDT generates reactive oxygen species (ROS), a key mediator of ultraviolet radiation (UVR)-induced photoaging, raising questions about its rejuvenating effects. Here, we employed a multi-omics approach to clarify this paradox. A UVR-induced hairless mouse model of photoaging was treated with ALA-PDT, followed by transcriptomic, proteomic, and metabolomic profiling of skin biopsies. In vitro, fibroblast senescence was induced by UV irradiation to evaluate ALA-PDT's protective effects. Mitochondrial function and citrate (CA) levels were assessed pre- and post-treatment. ALA-PDT significantly ameliorated photoaging phenotypes in mice, with multi-omics data revealing sustained improvements in epidermal structure, extracellular matrix integrity, and immune responses. Key mechanistic findings included ALA-PDT-induced mitohormesis and tricarboxylic acid cycle reprogramming, notably reduced intracellular CA. In vitro, low-dose ALA-PDT downregulated senescence markers and CA content in UV-stressed fibroblasts, concomitant with upregulated mitohormesis markers. These effects were abrogated by inhibiting mitochondrial ROS, suggesting ROS-dependent mitohormetic signaling. Collectively, our data demonstrate that low-dose ALA-PDT alleviates photoaging by mitigating cellular senescence via mitohormesis-mediated CA reduction, offering a novel metabolic intervention strategy for age-related skin disorders.

BACKGROUND:5-Aminolevulinic acid photodynamic therapy (ALA-PDT) is a promising treatment for glioblastoma multiforme (GBM), the most malignant form of brain cancer. However, challenges persist. The heterogeneous and invasive nature of GBM frequently results in hypoxic regions within the tumor and its periphery, where the efficacy of PDT may be diminished. Consequently, it is imperative to explore combination treatments that enhance PDT-induced cell death. Resveratrol (Res) is a natural phenolic compound recognized for its anti-inflammatory and anti-tumor properties against glioblastoma cells. Given these considerations, the study employed sublethal-dose ALA-PDT to simulate the reduced efficacy of ALA-PDT commonly observed in GBM and explored the effects of combining Res with sublethal-dose ALA-PDT on glioblastoma cells in vitro. METHODS:Human glioblastoma U251 and U87 cells were treated with Res and/or sublethal-dose ALA-PDT. Cell viability, migration inhibition, and apoptosis were assessed using the CCK-8 assay, colony-forming assay, scratch assay, Calcein-AM/PI, and TUNEL staining. Western blotting was performed to detect the expression levels of proteins involved in the ERK1/2 and mTOR signaling pathways and autophagy. RESULTS:Res inhibited the viability of U251 and U87 cells in a dose- and incubation time-dependent manner. Compared to single treatments, the combination of sublethal-dose ALA-PDT and Res reduced cell viability and migration and induced apoptosis. This combined treatment suppressed the ERK1/2 and mTOR signaling pathways. Additionally, Res enhanced ALA-PDT-induced autophagy-dependent cell death, as autophagy inhibitors partially reversed the decrease in cell viability resulting from the combined treatment. CONCLUSION:This study demonstrates that the combination of Res and ALA-PDT enhances the inhibition of glioblastoma cell growth compared to the single treatments. The combined therapy can induce apoptosis and autophagy in GBM cells by suppressing the ERK1/2 and mTOR signaling pathways, providing a potential new treatment for GBM. However, in vivo validation and clinical trials are essential for fully evaluating the potential of this mechanism regarding translation into clinical application.

e21567 Background: The high global incidence of skin cancer severely impairs patients' quality of life and even poses a life-threatening risk. Traditional therapies carry severe local adverse reactions, long treatment courses and high recurrence rates. EN002 is a novel anticancer compound we developed based on the novel anticancer targets, DNA Replication-Initiation Proteins (DRIPs) that we have established. It selectively induces apoptosis of cancer cells but not normal cells and can eradicate tumors in mouse xenograft models. Phase II clinical study of EN002 gel for non-melanoma skin cancer (NMSC) and precancerous lesions in China and Australia is near completion, with an emphasis on actinic keratosis (AK) which is a common precancerous skin lesion with a risk of developing into skin cancer. Methods: This is a multicenter, multiple-arm, partially randomized, open-label, Phase I/II clinical study to evaluate the safety, tolerability and efficacy of EN002-gel in the treatment of adult patients with AK or NMSC including basal cell carcinoma (BCC), Bowen's disease (BD), and low-risk squamous cell carcinoma (SCC). In Phase I, dose escalation was performed using the BOIN design, encompassing six dose levels from 0.008 to 0.12 mg/cm², and 0.06 mg/cm² was confirmed as the recommended Phase II dose (RP2D). Two dosing frequencies at the RP2D are under investigation in Phase II: each dosing cycle consists of either 11 once-every-other-day doses or 14 once-daily doses, both with a 5-day drug-free period preceding the next cycle. Treatment duration was up to three cycles for patients with AK, and six cycles for patients with NMSC. Patients underwent 28-day and 56-day follow-up periods after the last dose for Phase I and Phase II, respectively. Results: Drug-related adverse events were predominantly Grade 1 or 2 local cutaneous reactions at the application sites, with no drug-related serious adverse events reported. In Phase I, lesions exhibited varying degrees of clearance with no disease progression observed. In the ongoing Phase II study, among the first 20 evaluable AK patients (Olson grades 1-3; 1-7 lesions on the face and/or limbs per patient) who completed the study, 90% (18/20) achieved complete lesion clearance either at the end of treatment or during the follow-up period. Among six evaluable patients with one or more BD lesions who completed the study, 66.7% (4/6) attained complete clinical clearance. Significant tumor shrinkage was also observed in patients with BCC and SCC, although complete clearance has not been achieved to date. Conclusions: The Phase I/II studies provided clinical evidence of a favorable benefit-risk profile of a novel topical therapy for patients with BD, BCC, SCC or AK, who represent unmet medical needs. Phase II drug treatment for AK is expected to be completed in May 2026 and new results will be presented at this meeting. Clinical trial information: China-CTR20221021; also Australian-ACTRN12623001219673.

Here, we present a protocol for establishing cutaneous squamous cell carcinoma (cSCC) in SKH-1 hairless mice using a chronic ultraviolet irradiation regimen, followed by treatment with topical 5-aminolevulinic acid photodynamic therapy (ALA-PDT). We describe steps for a 28-week UV induction schedule, standardized preparation and application of ALA cream, and precise parameters for light irradiation. The model recapitulates key stages of human photocarcinogenesis, providing a physiologically relevant system for investigating cSCC pathogenesis and assessing PDT efficacy in vivo. For complete details on the use and execution of this protocol, please refer to Chen et al.1

Background:Suboptimal adherence to first-line topical medications (eg, topical retinoids, benzoyl peroxide, and topical antibiotics) is a major barrier to effective acne vulgaris (AV) management. The influence of patients' pre-treatment expectations and concerns about adverse effects on adherence behavior remains inadequately quantified. Objective:To evaluate young patients' perceptions of acne and their expectations, concerns, and adherence regarding topical medications. Methods:A web-based cross-sectional survey was conducted from December 2023 to January 2024. Patients aged 16-29 with a history of AV and topical medication use were recruited. Data on demographics, disease perception, medication knowledge, usage patterns, and adherence were collected via a structured questionnaire and analyzed using descriptive and comparative statistics. Results:A total of 501 valid questionnaires were collected. Patients acquired their knowledge about acne through various channels, with dermatologists being the most reliable source of information. Although 82.83% of patients recognized AV as a chronic disease, substantial misconceptions regarding its etiology and treatment persisted. Topical medications were commonly used, most frequently adapalene (40.92%), tretinoin (32.93%), benzoyl peroxide (24.75%), and clindamycin (20.96%). However, patients demonstrated limited knowledge regarding the proper application. Expectations for the onset of topical medications were overly optimistic, whereas the actual duration of use was often inadequate. The information that respondents had the strongest desire to access included the side effects, method of use, onset time, and duration of use. Medication discontinuation was primarily attributed to perceived slow efficacy or concerns about adverse effects, which contributed to a relatively high recurrence rate following treatment cessation. Conclusion:Young patients demonstrated limited comprehension of AV and lacked knowledge of topical medications and their appropriate application, as well as unrealistic expectations regarding onset time. Enhanced education on the nature of AV, along with detailed instructions on topical medication use, is crucial for improving patients' disease awareness and treatment adherence.

Background Transdermal drug delivery technologies (TDDTs) enhance drug absorption and therapeutic outcomes in dermatology, yet standardized, evidence-based recommendations for their clinical application remain lacking. Objective To provide expert consensus recommendations on the clinical application of TDDTs, with a focus on fractional lasers and microneedles. Methods A multidisciplinary panel of 25 experts systematically reviewed current literature and clinical practices. The consensus was developed using the Grading of Recommendations Assessment, Development and Evaluation framework to assess evidence quality and recommendation strength and the modified Delphi method to achieve expert agreement. Results Evidence-based recommendations were formulated for the use of TDDTs in a variety of dermatological conditions, including cutaneous malignancies and precancerous lesions, viral warts, inflammatory and autoimmune skin diseases, and cosmetic indications. Conclusion Fractional lasers and microneedles are valuable transdermal delivery tools for dermatological therapy. This expert consensus provides practical, evidence-based guidance to support their safe and effective clinical use.

Background Vitiligo profoundly compromises patients' quality of life, yet camouflage therapy-an important adjunctive intervention-remains underutilized. Clinical observations reveal marked differences in the performance of various camouflage agents under Wood's lamp examination, suggesting potential disparities in their ultraviolet (UV) protective capabilities. However, evidence-based guidance for patients and clinicians regarding product selection is currently lacking.Objective This study aimed to quantify the photoprotective properties of two agents (A/B) and assess the dual benefits of concealment plus photoprotection.Methods A two-phase prospective cohort study was conducted. First, 31 healthy volunteers evaluated minimal erythema dose (MED), sun protection factor (SPF), minimal persistent pigment darkening dose (MPPD), and UVA protection factor (UVAPF) for Agents A/B. Second, 36 progressive non-segmental facial vitiligo patients were randomized to use Agent A or B for one month. Primary outcome was Dermatology Life Quality Index (DLQI) change from baseline. Within-group changes were analyzed using paired t-tests; between-group post-treatment DLQI was compared using ANCOVA with baseline DLQI as a covariate.Results Agent A demonstrated significant UV protective efficacy (SPF = 29.87 +/- 2.31; UVAPF = 3.93 +/- 0.95; PA+), whereas Agent B exhibited no measurable photoprotection. Baseline DLQI scores showed no significant difference between groups (16.18 +/- 2.94 vs. 15.71 +/- 4.00; p = 0.70). After one month, both groups showed significant within-group DLQI improvements. After adjusting for baseline DLQI using ANCOVA, the Agent A group demonstrated a trend toward greater improvement compared to the Agent B group (adjusted mean difference: 1.78, 95% CI: -0.01 to 3.57, p = 0.051), with improvement rates of 46.0% and 29.7%, respectively.Conclusion Camouflage agents enhance vitiligo patients' quality of life. Agents combining concealment and sun protection provide dual benefits-immediate masking and enhanced photoprotection-and are associated with a trend toward superior short-term outcomes. Clinicians should prioritize sun-protective camouflage products in comprehensive management plans.

ABSTRACT Background Age‐related dermal collagen depletion compromises skin elasticity, manifesting as tissue laxity and loss of facial structural definition. The pursuit of facial tightening has driven vigorous development of non‐surgical rejuvenation modalities, with microfocused ultrasound emerging as a clinically validated intervention for restoring cutaneous firmness. Objectives This study aimed to assess the efficacy and safety of novel intelligent microfocused ultrasound (iMFU) in reversing facial aging and improving skin sagging. Methods Participants with facial aging and sagging were enrolled and iMFU treatment was performed on the randomized middle and lower hemiface. The length, angle, and area of the nasolabial folds and perioral wrinkles, the angle of the side face and the lower face, melanin index (MI), and erythema index (EI) were recorded and evaluated at 1st and 2nd month post‐treatment. Side effects and subjects' satisfaction scores were evaluated during treatment and each follow‐up visit. Results 32 patients successfully completed the study. Quantitative analysis revealed obvious changes following iMFU treatment: the average length of perioral wrinkles and nasolabial folds on iMFU sides decreased by 7.2% ( p < 0.001) and 18.5% ( p = 0.011) in month‐2 follow‐up time. IMFU treatment also showed significant improvements in nasolabial fold angle (from 29.5 ± 4.3 to 30.7 ± 2.1) and area (37.5 ± 0.6 to 35.1 ± 1.2). Perioral folds achieved a similar therapeutic effect. Side face angle a demonstrated a significant increase from 12° ± 2.6° to 13° ± 1.5°, while the mandibular angle b similarly increased from 16° ± 2.4° to 18° ± 1.9° on iMFU sides. In addition, iMFU sides had greater benefits in improving MI and EI than the control sides. The subjects' satisfaction scores in iMFU sides were significantly higher than that in control sides. Except for 1 patient who experienced toothache after iMFU treatment, no persistent or serious side effects occurred in the other subjects. Conclusion IMFU treatment demonstrates both safety and efficacy for facial rejuvenation, with clinically validated outcomes in skin tightening, facial contour refinement, and skin tone improvement. This non‐invasive approach delivers significant aesthetic enhancement across multiple parameters of facial aging.

Actinic keratosis is a precancerous skin lesion caused by long-term sun exposure, and may progress to cutaneous squamous cell carcinoma. Bowen disease is a squamous cell carcinoma in situ of the epidermis. Differential diagnosis of actinic keratosis, Bowen disease and cutaneous squamous cell carcinoma, as well as early diagnosis of cutaneous squamous cell carcinoma, has always been research hotspots. This review summarizes biomarkers related to the malignant progression of actinic keratosis, with a view to providing a reference for early clinical diagnosis.

Acne vulgaris, a prevalent chronic inflammatory skin disorder, is often characterized by hyperactive sebaceous glands and excessive sebum production, presenting a significant therapeutic challenge. While 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is clinically effective in treating moderate to severe acne, the molecular mechanisms underlying its therapeutic effects remain largely unexplored. In this study, we investigated the impact of ALA-PDT on lipid metabolism in an acne-like mouse model and in immortalized human sebocytes (XL-i-20), focusing on the role of the OLR1-Wnt/β-catenin pathway. We employed transcriptomic analysis, lipid staining, and gene silencing techniques to dissect the molecular interactions induced by ALA-PDT. Our findings revealed that ALA-PDT significantly reduces lipogenesis by upregulating OLR1, which in turn suppresses the SREBP1-FAS axis, thereby decreasing lipid accumulation in sebocytes. Furthermore, activation of the OLR1-Wnt/β-catenin pathway was essential for these lipogenic effects, as silencing OLR1 or activating Wnt/β-catenin signaling reversed lipogenesis inhibition. This study elucidates a novel mechanistic pathway in ALA-PDT-mediated acne treatment, highlighting OLR1 as a promising target for future therapeutic strategies.

Background HMME‐PDT has been proven to be safe and effective for treating port‐wine stains (PWS). However, due to the relatively high overall cost of a single session, particularly for patients with large‐area PWS, some patients may forego treatment due to financial constraints. There is a need to explore new treatment methods for HMME‐PDT for large‐area PWS. Objective To investigate the safety and effectiveness of modified HMME‐PDT, aiming to provide a more efficient treatment option for large‐area PWS. Methods Patients with large‐area PWS were treated with modified HMME‐PDT. Modified HMME‐PDT consists of two treatment stages, with the first stage being equivalent to the traditional HMME‐PDT for partial lesions, continuously followed by the second stage in which the treatment device heads were moved to remaining untreated lesions for irradiation. Initially, all patients received an intravenous injection of 5 mg/kg HMME, and then the partial lesions of the patients were exposed to 532 nm LED green light after 10 min. The irradiation power density ranged between 80 and 100 mW/cm2. Treatment parameters in the second stage remained consistent with the first stage. Efficacy was evaluated 2 months after treatment, and adverse reactions were recorded and compared. Results A total of 27 patients with large‐area PWS were included in the study. In Stage 1, 1 patient (3.7%) achieved cured, 5 patients (18.6%) achieved good efficacy, 12 patients (44.4%) achieved alleviation, and 9 patients (33.3%) showed no effect, with a total effective rate of 66.7%. In the second stage treatment, 1 patient (3.7%) achieved cured, 6 patients (22.2%) achieved good efficacy, 9 patients (33.3%) achieved alleviation, and 11 patients (40.7%) showed no effect, with a total effective rate of 59.3%. No statistically significant difference in efficacy between the two stages was observed (p > 0.05). The occurrence and severity of adverse reactions did not differ significantly (p > 0.05). Conclusion Modified HMME‐PDT can provide effective treatment for double the area in a single session for patients with large‐area PWS, potentially reducing the cost and time per unit area.

Spatial transcriptomics (ST) differs from traditional transcriptomic approaches by retaining tissue architecture and enabling the spatial mapping of gene expression. As a promising method, ST has been applied to skin diseases in recent years, such as psoriasis, atopic dermatitis, and skin tumors. This review provides a comprehensive overview of ST in skin diseases. We first summarize the mainstream ST technologies and the key factors influencing platform selection for skin disease research. We then outline recent advances in the application of ST in dermatology, highlighting its ability to systematically reveal in situ cellular interactions and regional heterogeneity. We also discuss how ST can guide therapeutic strategies for skin diseases through target discovery, response prediction, and the elucidation of spatially resolved mechanisms underlying treatment resistance. These spatial findings have also informed the development of novel targeted therapies and the optimization of existing treatment regimens for various skin disorders. In summary, ST offers new perspectives and powerful tools for understanding the regulatory mechanisms of skin physiology, thereby promoting the clinical translation of precision diagnostic and therapeutic strategies. A better understanding of ST applications in skin diseases will enable more effective treatments.

Photobiomodulation therapy (PBMT) is a safe and effective option for multiple skin diseases. To promote standardized clinical use, this expert consensus was developed by 35 dermatology experts through 2 rounds of Delphi surveys and addressed 19 clinical questions with a consensus degree of over 80.0%. This consensus summarizes current evidence on PBMT’s mechanisms of action, indications, contraindications, treatment parameters, and adverse event management. Although encouraging outcomes have been observed regarding acne vulgaris, photoaging, alopecia, and other dermatologic conditions, considerable variability in treatment protocols and the scarcity of high-quality, large-scale clinical trials continue to limit broader clinical adoption. This consensus provides evidence-based and practical guidance to support the safe and effective incorporation of PBMT into dermatologic practice in China.