Pyroptosis-related gene signature elicits immune response in rosacea.

Rosacea is a complex chronic inflammatory skin disorder with high morbidity. Pyroptosis is known as a regulated inflammatory cell death. While its association with immune response to various inflammatory disorders is well established, little is known about its functional relevance of rosacea. So, we aimed to explore and enrich the pathogenesis involved in pyroptosis-related rosacea aggravations. In this study, we evaluated the pyroptosis-related patterns of rosacea by consensus clustering analysis of 45 ferroptosis-related genes (FRGs), with multiple immune cell infiltration analysis to identify the pyroptosis-mediated immune response in rosacea using GSE65914 dataset. The co-co-work between PRGs and WGCNA-revealed hub genes has established using PPI network. FRG signature was highlighted in rosacea using multi-transcriptomic and experiment analysis. Based on this, three distinct pyroptosis-related rosacea patterns (non/moderate/high) were identified, and the notably enriched pathways have revealed through GO, KEGG and GSEA analysis, especially immune-related pathways. Also, the XCell/MCPcount/ssGSEA/Cibersort underlined the immune-related signalling (NK cells, Monocyte, Neutrophil, Th2 cells, Macrophage), whose hub genes were identified through WGCNA (NOD2, MYD88, STAT1, HSPA4, CXCL8). Finally, we established a pyroptosis-immune co-work during the rosacea aggravations. FRGs may affect the progression of rosacea by regulating the immune cell infiltrations. In all, pyroptosis with its mediated immune cell infiltration is a critical factor during the development of rosacea.

Integrated bioinformatics analysis and experimental validation identifies CPE as a potential biomarker and therapeutic target for skin aging.

Ageing is an inevitable biological process characterized by progressive decline in physiological functions. It is a complex natural phenomenon that will cause structural and functional decline. Despite substantial progress in understanding the mechanism of ageing, both predictive biomarkers and preventive therapies remain limited. Using Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning techniques, we identified Carboxypeptidase E (CPE) as a pivotal marker of skin ageing, based on ageing-related bulk transcriptome and single-cell transcriptome data. Next, our investigation reveals downregulation of CPE in replicative, UVA-induced, and H2O2-induced senescent human dermal fibroblast cells (HDFs). Furthermore, shRNA-mediated CPE knockdown induced HDFs senescence, and overexpression of CPE delayed HDFs senescence. Moreover, downregulated CPE inhibits collagen synthesis and induces inflammation, highlighting its potential as a therapeutic target for skin ageing. In conclusion, our study demonstrated that CPE functions as a predictor and optional target for therapeutic intervention of skin ageing.

Association of air pollution with incidence of elderly-onset seborrheic dermatitis: A prospective cohort study in UK Biobank.

BACKGROUND: Elderly-onset seborrheic dermatitis (SD) seriously affects the quality of life. However, associations between air pollution exposures and elderly-onset SD incidence have not been elucidated. OBJECTIVES: Investigate air pollution's role in the incidence of elderly-onset SD. METHODS: We engaged a prospective cohort analysis utilizing the UK Biobank database. Exposure data for specific air pollutants (PM2.5, PM2.5-10, NOX, NO2, and PM10) spanning various years was incorporated. Through a composite air pollution score constructed from five pollutants and employing Cox proportional hazards models, the relationship between pollution and SD was delineated. RESULTS: Our examination of 193,995 participants identified 3,363 SD cases. Higher concentrations of specific pollutants, particularly in the upper quartile (Q4), were significantly linked to an elevated SD risk. Notably, PM2.5, PM10, NO2, and NOX exhibited hazard ratios of 1.11, 1.15, 1.22, and 1.15, respectively. The correlation was further solidified with a positive association between air pollution score increments and SD onset. Intriguingly, this association was accentuated in certain demographics, including younger males, the socioeconomically deprived, smokers, daily alcohol consumers, and those engaging in regular physical activity. CONCLUSIONS: Our findings revealed that air pollution exposures were associated with elderly-onset SD incidence. These results emphasize the importance of preventing environmental exposures to the risk of SD development.

GBP5 exacerbates rosacea-like skin inflammation by skewing macrophage polarization towards M1 phenotype through the NF-κB signalling pathway.

BACKGROUND: Rosacea is a chronic inflammatory skin disease with increased macrophage infiltration. However, the molecular mechanism remains unclear. OBJECTIVES: To determine the significance of macrophage infiltration, and the correlation between Guanylate-binding protein 5 (GBP5) and polarization of macrophages in rosacea-like inflammation. METHODS: Here we tested the hypothesis that Guanylate-binding protein 5 (GBP5) aggravates rosacea-like skin inflammation by promoting the polarization of the M1 macrophages through the NF-κB signalling pathway. We depleted macrophage by injecting clodronate-containing liposomes. We next explored the association between GBP5 and macrophage in rosacea tissue through transcriptome analysis and immunofluorescence analysis. We evaluated the severity of rosacea-like skin inflammation when BALB/c mice were injected with GBP5 siRNA intradermally daily for three consecutive days. At last, to study the causality of knocking down GBP5-blunted M1 macrophage polarization, THP-1 cell was treated with GBP5 siRNA. RESULTS: Macrophage depletion ameliorated rosacea-like skin inflammation in mice, implying the important role of macrophages in rosacea. Based on the transcriptome analysis, Guanylate-binding protein 5 (GBP5) was identified as hub gene that was associated with macrophage infiltration in rosacea. Next, we found that GBP5 expression was significantly upregulated in rosacea tissues and positively correlated with macrophage infiltration, the immunofluorescence analysis revealed the co-localization between GBP5 and macrophages. In vivo, silencing of GBP5 attenuated rosacea-like skin inflammation in the LL-37-induced mouse model and suppressed the expression of M1 signature genes such as IL-6, iNOS and TNF-a. In vitro, knocking down GBP5 significantly blunted the polarization of the M1 macrophages partly by repressing the activation of the NF-κB signalling pathways. CONCLUSIONS: Together, our study revealed the important role of macrophages in rosacea and identified GBP5 as a key regulator of rosacea by inducing M1 macrophage polarization via NF-κB signalling pathways.

An M0 macrophage-related prognostic model for hepatocellular carcinoma.

BACKGROUND: The role of M0 macrophages and their related genes in the prognosis of hepatocellular carcinoma (HCC) remains poorly characterized. METHODS: Multidimensional bioinformatic methods were used to construct a risk score model using M0 macrophage-related genes (M0RGs). RESULTS: Infiltration of M0 macrophages was significantly higher in HCC tissues than in normal liver tissues (P = 2.299e-07). Further analysis revealed 35 M0RGs that were associated with HCC prognosis; two M0RGs (OLA1 and ATIC) were constructed and validated as a prognostic signature for overall survival of patients with HCC. Survival analysis revealed the positive relationship between the M0RG signature and unfavorable prognosis. Correlation analysis showed that this risk model had positive associations with clinicopathological characteristics, somatic gene mutations, immune cell infiltration, immune checkpoint inhibitor targets, and efficacy of common drugs. CONCLUSIONS: The constructed M0RG-based risk model may be promising for the clinical prediction of prognoses and therapeutic responses in patients with HCC.

A new survival model based on ion channel genes for prognostic prediction in hepatocellular carcinoma.

Accumulating studies revealed the vital role of ion channels in cancers, but the prognosis role of ion channels in hepatocellular carcinoma (HCC) remains limited. Here, we developed and validated an ion channel signature for prognostic prediction of HCC patients. In total, 35 differential expressed ion channel genes (DEChannelGs) were identified in HCC and a novel ion channel risk model was established for HCC prognosis prediction using the TCGA cohort, which was validated using the ICGC cohort. Moreover, this risk model was an independent prognostic factor and was associated with the immune microenvironment in HCC. Finally, the mRNA and protein levels of ANO10 and CLCN2 were prominently up-regulated and were related to the poor prognosis of HCC patients. Taken together, these results indicated a novel ion channel risk model as a prognostic biomarker for HCC patients and provided further insight into its immunoregulatory mechanism in HCC progression.

Exploring metformin as a candidate drug for rosacea through network pharmacology and experimental validation.

Rosacea is a common chronic inflammatory disease that affects the middle of the face. Due to the unclear pathogenesis, the effective treatment options for rosacea remain limited. In this study, weighted gene co-expression network analyses (WGCNA) identified three rosacea-related hub modules, which were involved in immune-, metabolic- and development- related signaling pathways. Next, the key genes from green and brown modules were submitted to CMap database for drug prediction and metformin was identified as a candidate drug for rosacea. Moreover, network pharmacology analysis identified pharmacological targets of metformin and demonstrated that metformin could help in treating rosacea partly by modulating inflammatory and angiogenesis signaling pathways. Finally, we verified the therapeutic role and mechanism of metformin on rosacea in vivo and vitro. We found that metformin treatment significantly improved rosacea-like skin lesions including immune cells infiltration, cytokines/chemokines expression and angiogenesis. Moreover, metformin suppressed LL37- and TNF-α-induced the ROS production and MAPK-NF-κB signal activation in keratinocytes cells. In conclusion, our findings identified and verified metformin as a novel therapeutic candidate for rosacea, and it alleviates the pathological symptoms, possibly by suppressing inflammatory responses, angiogenesis in rosacea.

EPDR1 correlates with immune cell infiltration in hepatocellular carcinoma and can be used as a prognostic biomarker.

Hepatocellular carcinoma (HCC) has high mortality rate and is a serious disease burden globally. EPDR1 (ependymin related 1) is a member of piscine brain glycoproteins and is involved in cell adhesion. The gene expression, prognostic, and clinicopathological related data for EPDR1 were obtained from multiple transcriptome databases. Protein level of EPDR1 in HCC was verified using human protein atlas and CPTAC databases. EPDR1 co-expressed genes were identified using LinkedOmics. Functional analysis of the co-expressed genes was performed using gene set enrichment analysis, Gene Ontology, and KEGG. Statistical analysis was conducted in R. The relationship between EPDR1 expression and immune cell infiltration was analyzed using TIMER and CIBERSORT. The expression of EPDR1 was found to be significantly higher in HCC than in normal tissues. Further, EPDR1 level was correlated with advanced stage of HCC. EPDR1 was associated with multiple signaling, as well as cancer and apoptotic pathways. Further, EPDR1 expression was significantly correlated with purity and infiltration levels of various immune cells as well as immune signatures. This is the first study to report the role of EPDR1 in HCC. EPDR1 can be used as a novel prognostic biomarker as well as an effective target for diagnosis and treatment in HCC.

Skincare Habits and Rosacea in 3,439 Chinese Adolescents: A University-based Cross-sectional Study.

The pathogenesis of rosacea remains unclear but has been reported to correlate with skin barrier function. The objective of this study was to elucidate the skincare habits of Chinese adolescents and determine the relationship between skincare habits and rosacea. A university-based cross-sectional investigation included 310 rosacea cases and 3,129 healthy controls who underwent health examinations and completed a questionnaire about daily skincare habits. Fitzpatrick skin phototype IV is a protective factor against rosacea (adjusted adds ratio (aOR) 0.40; 95% confidence interval (CI) 0.22-0.72). Long bath duration (≥ 11 min, aOR 2.60; 95% CI 1.01-6.72) and frequent use of facial cleansers (≥ 2 times/day, aOR 1.70; 95% CI 1.17-2.36) were positively associated with rosacea, but bath frequency (p = 0.22), water temperature (p = 0.53), and sun protection (p = 0.65) were not associated with rosacea. Inappropriate skincare habits, including extended bath durations and frequent use of facial cleansers, significantly increase the risk of rosacea in Chinese adolescents.

[Role of DNA methyltransferase 1 in mouse skin aging].

OBJECTIVE: To explore the role ofDNA methyltransferase 1 (DNMT1) in mouse skin aging.
 Methods: Epidermal conditional K14 Cre-mediated DNA methyltransferase 1 (DNMT1) knockout mice (Mut group, n=4) and the littermate normal mice with the same age (WT group) n=4) were used in this study. HE staining was used to detect the pathological changes of skin; the changes of number in the dermal elastic fibers were detected by Gomori aldehyde fuchsin staining, the number of 5-bromo-2-deoxyuridine (BrdU)-labeled transit amplifying cells (TAC) in epidermis were detected by immunohistochemical staining; the number of chlorodeoxyuridine (CldU)-label-retaining cells (LRC) in epidermis were detected by immunofluorescent staining.
 Results: Compared with the WT group, the skin showed premature aging symptoms in the Mut group concomitant with the decreased epidermal thickness as well as the number of dermal collagen fibers, while the increased dermal elastic fiber fracture. Compared with the WT group, the number of TAC in the epidermis was significantly increased (P<0.05), and the number of LRC was significantly decreased (P<0.05) in the Mut group.
 Conclusion: The phenotype of skin premature aging in epidermal stem cell conditional DNMT1-knockout mice suggests an important role of DNMT1 in skin aging.

Structural and Functional Diversity of Peptide Toxins from Tarantula Haplopelma hainanum (Ornithoctonus hainana) Venom Revealed by Transcriptomic, Peptidomic, and Patch Clamp Approaches.

Spider venom is a complex mixture of bioactive peptides to subdue their prey. Early estimates suggested that over 400 venom peptides are produced per species. In order to investigate the mechanisms responsible for this impressive diversity, transcriptomics based on second generation high throughput sequencing was combined with peptidomic assays to characterize the venom of the tarantula Haplopelma hainanum. The genes expressed in the venom glands were identified, and the bioactivity of their protein products was analyzed using the patch clamp technique. A total of 1,136 potential toxin precursors were identified that clustered into 90 toxin groups, of which 72 were novel. The toxin peptides clustered into 20 cysteine scaffolds that included between 4 and 12 cysteines, and 14 of these groups were newly identified in this spider. Highly abundant toxin peptide transcripts were present and resulted from hypermutation and/or fragment insertion/deletion. In combination with variable post-translational modifications, this genetic variability explained how a limited set of genes can generate hundreds of toxin peptides in venom glands. Furthermore, the intraspecies venom variability illustrated the dynamic nature of spider venom and revealed how complex components work together to generate diverse bioactivities that facilitate adaptation to changing environments, types of prey, and milking regimes in captivity.

Physiological and biochemical analysis to reveal the molecular basis for black widow spiderling toxicity.

The early research found that the spiderlings of black widow spider (Latrodectus tredecimguttatus) exhibited obvious toxicity to animals. The present work performed a systematical analysis of the aqueous extract of newborn black widow spiderlings. The extract was shown to contain 69.42% of proteins varying in molecular weights and isoelectric points. Abdominal injection of the extract into mice and cockroaches caused obvious poisoning symptoms as well as death, with LD50 being 5.30 mg/kg in mice and 16.74 µg/g in Periplaneta americana. Electrophysiological experiments indicated that the extract at a concentration of 10 µg/mL could completely block the neuromuscular transmission in isolated mouse nerve-hemidiaphragm preparations within 21 ± 1.5 min, and 100 µg/mL extract could inhibit a certain percentage of voltage-activated Na⁺, K⁺, and Ca²âº channel currents in rat dorsal root ganglion neurons. These results demonstrate that the spiderlings are rich in neurotoxic components, which play important roles in the spiderling toxicity.

Physiological and biochemical characterization of egg extract of black widow spiders to uncover molecular basis of egg toxicity.

BACKGROUND: Black widow spider (L. tredecimguttatus) has toxic components not only in the venomous glands, but also in other parts of the body and its eggs. It is biologically important to investigate the molecular basis of the egg toxicity. RESULTS: In the present work, an aqueous extract was prepared from the eggs of the spider and characterized using multiple physiological and biochemical strategies. Gel electrophoresis and mass spectrometry demonstrated that the eggs are rich in high-molecular-mass proteins and the peptides below 5 kDa. The lyophilized extract of the eggs had a protein content of 34.22% and was shown to have a strong toxicity towards mammals and insects. When applied at a concentration of 0.25 mg/mL, the extract could completely block the neuromuscular transmission in mouse isolated phrenic nerve-hemidiaphragm preparations within 12.0 ± 1.5 min. Using whole-cell patch-clamp technique, the egg extract was demonstrated to be able to inhibit the voltage-activated Na+, K+ and Ca2+ currents in rat DRG neurons. In addition, the extract displayed activities of multiple hydrolases. Finally, the molecular basis of the egg toxicity was discussed. CONCLUSIONS: The eggs of black widow spiders are rich in proteinous compounds particularly the high-molecular-mass proteins with different types of biological activity The neurotoxic and other active compounds in the eggs are believed to play important roles in the eggs' toxic actions.

Hematological parameters as diagnostic biomarkers for patients with rosacea.

Rosacea is a chronic inflammatory skin disease. Systemic inflammation plays a vital role in the pathogenesis of rosacea. Many studies have reported hematological parameters as biomarkers for diseases with inflammatory processes. However, the diagnostic value of hematological parameters in rosacea remains a puzzle. This study involved 462 patients with rosacea, including erythematotelangiectatic rosacea (ETR, n = 179), papulopustular rosacea (PPR, n = 250), and phymatous rosacea (PhR, n = 33), and 924 healthy control subjects. Demographic, clinical, and laboratory information was collected and compared between rosacea subtypes. The hematological parameters of the patients and the healthy controls were compared retrospectively. The platelet volume (MPV) and platelet crit (PCT) were significantly upregulated, and the lower red cell distribution width (RDW) was significantly downregulated in rosacea compared to healthy controls, and they were identified as the diagnostic biomarkers for rosacea with area under the curve values of 0.828, 0.742, and 0.787, respectively. Comparing the hematological parameters among the three rosacea subtypes, we found that platelet-to-lymphocyte ratio and platelet-to-neutrophil ratio values in the ETR group were significantly higher than those in the PPR and PhR groups. The correlation between hematological parameters and clinical scores showed that RDW was negatively correlated with the Clinician Erythema Assessment score. However, there was no significant correlation between the Investigator Global Assessment score and hematological parameters. In conclusion, PCT, MPV, and RDW have diagnostic value for rosacea, and RDW is correlated with the severity of rosacea erythema, implying the potential applications of PCT, MPV, and RDW in the diagnosis and monitoring of rosacea.

WTAP Mediated N6-methyladenosine RNA Modification of ELF3 Drives Cellular Senescence by Upregulating IRF8.

N6-methyladenosine (m6A), the most prevalent posttranscriptional RNA modification, involved in various diseases and cellular processes. However, the underlying mechanisms of m6A regulation in skin aging are still not fully understood. In this study, proteomics analysis revealed a significant correlation between Wilms' tumor 1-associating protein (WTAP) expression and cellular senescence. Next, upregulated WTAP was detected in aging skin tissues and senescent human dermal fibroblasts (HDFs). Functionally, overexpressed WTAP induced senescence and knockdown of WTAP rescued senescence of HDFs. Mechanistically, WTAP directly targeted ELF3 and promoted its expression in an m6A-dependent manner. Exogenous-ELF3 overexpression evidently reversed shWTAP-suppressed fibroblast senescence. Furthermore, ELF3 induced IRF8-mediated senescence-associated secretory phenotype (SASP) by binding to the (-817 to -804) site of the IRF8 promoter directly. In vivo, overexpression of WTAP evidently increased senescence cells in skin and induced skin aging. In summary, these findings revealed the critical role of WTAP-mediated m6A modification in skin aging and identified ELF3 as an important target of m6A modification in HDFs senescence, providing a new idea for delaying the aging process.

A novel CD8+ T cell-related gene signature as a prognostic biomarker in hepatocellular carcinoma.

CD8+ T cells have great roles in tumor suppression and elimination of various tumors including hepatocellular carcinoma (HCC). Nonetheless, potential prognostic roles of CD8+ T cell-related genes (CD8Gs) in HCC remains unknown. In our study, 416 CD8Gs were identified in HCC, which were enriched in inflammatory and immune signaling pathways. Using The Cancer Genome Atlas dataset, a 5-CD8Gs risk model (KLRB1, FYN, IL2RG, FCER1G, and DGKZ) was constructed, which was verified in International Cancer Genome Consortium and gene expression omnibus datasets. Furthermore, we found that overall survival was independently correlated with the CD8Gs signature, and it was associated with immune- and cancer-related signaling pathways and immune cells infiltration. Finally, drug sensitivity data indicated that 10 chemotherapeutic drugs held promise as therapeutics for HCC patients with high-risk. In conclusion, multi-databases analysis showed that 5-CD8Gs and their signature could be an indicator to predict candidate drugs for HCC therapy.

Integrated Omics Reveal the Molecular Characterization and Pathogenic Mechanism of Rosacea.

Recent efforts have described the transcriptomic landscape of rosacea. However, little is known about its proteomic characteristics. In this study, the proteome and phosphoproteome of lesional skin, paired nonlesional skin, and healthy skin were analyzed by liquid chromatography coupled with tandem mass spectrometry. The molecular characteristics and potential pathogenic mechanism of rosacea were demonstrated by integrating the proteome, phosphoproteome, and previous transcriptome. The proteomic data revealed a significant upregulation of inflammation- and axon extension-related proteins in lesional skin and nonlesional skin versus in healthy skin, implying an inflammatory and nerve-hypersensitive microenvironment in rosacea skin. Of these, axon-related proteins (DPYSL2 and DBNL) were correlated with the Clinician's Erythema Assessment score, and neutrophil-related proteins (ELANE and S100A family) were correlated with the Investigator's Global Assessment score. Moreover, comorbidity-related proteins were differentially expressed in rosacea; of these, SNCA was positively correlated with Clinician's Erythema Assessment score, implying a potential correlation between rosacea and comorbidities. Subsequently, the integrated proteome and transcriptome demonstrated consistent immune disturbances at both the transcriptional and protein levels. The integrative analysis of the proteome and phosphoproteome revealed the key transcription factor network and kinase network that drive the dysregulation of immunity and vasculature in rosacea. In conclusion, our multiomics analysis enables more comprehensive insight into rosacea and offers an opportunity for, to our knowledge, previously unreported treatment strategies.

Downregulated SPESP1-driven fibroblast senescence decreases wound healing in aged mice.

BACKGROUND: Human dermal fibroblasts (HDFs) are essential in the processes of skin ageing and wound healing. However, the underlying mechanism of HDFs in skin healing of the elderly has not been well defined. This study aims to elucidate the mechanisms of HDFs senescence and how senescent HDFs affect wound healing in aged skin. METHODS: The expression and function of sperm equatorial segment protein 1 (SPESP1) in skin ageing were evaluated via in vivo and in vitro experiments. To delve into the potential molecular mechanisms by which SPESP1 influences skin ageing, a combination of techniques was employed, including proteomics, RNA sequencing, immunoprecipitation, chromatin immunoprecipitation and liquid chromatography-mass spectrometry analyses. Clearance of senescent cells by dasatinib plus quercetin (D+Q) was investigated to explore the role of SPESP1-induced senescent HDFs in wound healing. RESULTS: Here, we define the critical role of SPESP1 in ameliorating HDFs senescence and retarding the skin ageing process. Mechanistic studies demonstrate that SPESP1 directly binds to methyl-binding protein, leading to Decorin demethylation and subsequently upregulation of its expression. Moreover, SPESP1 knockdown delays wound healing in young mice and SPESP1 overexpression induces wound healing in old mice. Notably, pharmacogenetic clearance of senescent cells by D+Q improved wound healing in SPESP1 knockdown skin. CONCLUSIONS: Taken together, these findings reveal the critical role of SPESP1 in skin ageing and wound healing, expecting to facilitate the development of anti-ageing strategies and improve wound healing in the elderly.

Quercetin attenuates inflammation in rosacea by directly targeting p65 and ICAM-1.

AIMS: Rosacea is an inflammatory skin disease with immune and vascular dysfunction. Although there are multiple treatment strategies for rosacea, the clinical outcomes are unsatisfactory. MAIN METHODS: Combining transcriptome data and the Connectivity Map database quercetin was identified as a novel candidate for rosacea. Next, the therapeutic efficacy of quercetin was substantiated through proteomic analyses, in vivo experiments, and in vitro assays. Additionally, the utilization of DARTS, molecular docking and experimental verification revealed the therapeutic mechanisms of quercetin. KEY FINDINGS: Treatment with quercetin resulted in the following effects: (i) it effectively ameliorated rosacea-like features by reducing immune infiltration and angiogenesis; (ii) it suppressed the expression of inflammatory mediators in HaCaT cells and HDMECs; (iii) it interacted with p65 and ICAM-1 directly, and this interaction resulted in the repression of NF-κB signal and ICAM-1 expression in rosacea. SIGNIFICANCE: We show for the first time that quercetin interacted with p65 and ICAM-1 directly to alleviated inflammatory and vascular dysfunction, suggesting quercetin is a novel, promising therapeutic candidate for rosacea.

Targeting the STAT3/IL-36G signaling pathway can be a promising approach to treat rosacea.

BACKGROUND: Rosacea is an inflammatory skin disorder characterized by the release of inflammatory mediators from keratinocytes, which are thought to play a crucial role in its pathogenesis. Despite an incidence of approximately 5.5%, rosacea is associated with a poor quality of life. However, as the pathogenesis of rosacea remains enigmatic, treatment options are limited. OBJECTIVES: To investigate the pathogenesis of rosacea and explore new therapeutic strategies. METHODS: Transcriptome data from rosacea patients combined with immunohistochemical staining were used to investigate the activation of STAT3 in rosacea. The role of STAT3 activation in rosacea was subsequently explored by inhibiting STAT3 activation both in vivo and in vitro. The key molecules downstream of STAT3 activation were identified through data analysis and experiments. Dual-luciferase assay and ChIP-qPCR analysis were used to validate the direct binding of STAT3 to the IL-36G promoter. DARTS, in combination with experimental screening, was employed to identify effective drugs targeting STAT3 for rosacea treatment. RESULTS: STAT3 signaling was hyperactivated in rosacea and served as a promoter of the keratinocyte-driven inflammatory response. Mechanistically, activated STAT3 directly bind to the IL-36G promoter region to amplify downstream inflammatory signals by promoting IL-36G transcription, and treatment with a neutralizing antibody (α-IL36γ) could mitigate rosacea-like inflammation. Notably, a natural plant extract (pogostone), which can interact with STAT3 directly to inhibit its activation and affect the STAT3/IL36G signaling pathway, was screened as a promising topical medication for rosacea treatment. CONCLUSIONS: Our study revealed a pivotal role for STAT3/IL36G signaling in the development of rosacea, suggesting that targeting this pathway might be a potential strategy for rosacea treatment.