Psoriasis intervention by Huai’er (Trametes): unveiling novel targets via network pharmacology

Keyao LI; Ye SHU; Jing CHANG; Jianping TANG; Litao ZHANG; Zhu WEI

doi:10.19852/j.cnki.jtcm.2025.06.011

. 2025 Nov 24;45(6):1317–1329. doi: 10.19852/j.cnki.jtcm.2025.06.011

Psoriasis intervention by Huai’er (Trametes): unveiling novel targets via network pharmacology

Keyao LI ¹, Ye SHU ², Jing CHANG ², Jianping TANG ², Litao ZHANG ^3,^✉, Zhu WEI ^4,^✉

PMCID: PMC12711639 PMID: 41376224

Abstract

OBJECTIVE:

To investigate the therapeutic effects of Huai'er (Trametes) on psoriasis by identifying specific molecular targets and pathways involved in regulating keratinocyte behavior and immune responses.

METHODS:

Cellular experiments were conducted using human keratinocyte cell line (HaCaT) keratinocytes to evaluate the effects of Huai'er (Trametes) on cell proliferation, migration, and inflammatory factor expression. Additionally, an imiquimod (IMQ)-induced psoriasis-like mouse model was established to assess the therapeutic efficacy of Huai'er (Trametes) in vivo. Network pharmacology and transcriptomic analyses were performed to identify potential targets and pathways.

RESULTS:

Huai'er (Trametes) significantly inhibited HaCaT keratinocyte proliferation and migration in vitro, as evidenced by reduced 5-ethynyl-2′-deoxyuridine incorporation and wound healing rates. In the IMQ-induced psoriasis-like mouse model, Huai'er (Trametes) treatment reduced erythema, scaling, and dermal infiltration of inflammatory cells, demonstrating its efficacy in alleviating psoriasis symptoms. Network pharmacology and transcriptomic analyses identified signal transducer and activator of transcription 1 (STAT1) as a central target modulated by Huai'er (Trametes). This regulation was associated with decreased expression of pro-inflammatory cytokines, including interleukin-17A and tumor necrosis factor alpha, both in vitro and in vivo.

CONCLUSION:

This study demonstrates that Huai'er (Trametes) exerts therapeutic effects on psoriasis by modulating STAT1, thereby inhibiting keratinocyte proliferation and inflammatory responses. The findings provide a foundation for further research into the potential of Huai'er (Trametes) as a treatment for psoriasis.

Keywords: psoriasis, keratinocytes, inflammation, STAT1 transcription factor, network pharmacology, Huai'er (Trametes) , weighted gene co-expression network analysis

1. INTRODUCTION

Psoriasis is a chronic inflammatory skin disease characterized by excessive keratinocyte proliferation and immune dysregulation, affecting about 1%-3% of the global population.^1,2 Current treatments often have limited efficacy and potential side effects,^3,4 underscoring the need for novel therapeutic targets. Traditional Chinese Medicine plays an active role in psoriasis therapy.⁵ Huai'er (Trametes), a medicinal fungus used for over 1600 years,⁶ has recognized anti-tumor properties,^7,8 but its mechanisms in psoriasis remain unclear.

Network pharmacology is a method used to predict interactions between chemicals and targets, and it has made significant progress in drug development.^9,10 Through network pharmacology, we can screen for effective small-molecule compounds and target interactions related to the pathogenesis of psoriasis.^11,12 In addition, the application of transcriptomic techniques can help us uncover genes related to key pathways and gene modules.^13,14

The aim of this study is to elucidate the potential therapeutic targets and molecular mechanisms of Huai'er (Trametes) in psoriasis by integrating network pharmacology with transcriptomics. Active Huai'er (Trametes) ingredients and related targets were obtained from the high-throughput Experiment- and Reference-guided database (HERB) and Traditional Chinese Medicine Systems Pharmacology database (TCMSP) databases, while psoriasis-related genes were collected from GeneCards, Online Mendelian Inheritance in Man (OMIM), and Disgenet.^15,16 Their intersection was used to predict Huai'er (Trametes)’s anti-psoriatic targets.

Psoriasis microarray datasets were analyzed using weighted gene co-expression network analysis (WGCNA) to identify disease-related gene modules.^17,18 Differential expression, gene ontology (GO)/kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses,¹⁹ and protein-protein interaction network topology were applied to screen core therapeutic targets and key Huai'er (Trametes) components.

Focusing on the signal transducer and activator of transcription 1 (STAT1) gene, we will validate Huai'er (Trametes)’s efficacy via cellular and animal experiments, aiming to clarify its mechanism in treating psoriasis. This research is expected to offer new mechanistic insights, therapeutic targets, and strategies for personalized psoriasis management.

2. MATERIALS AND METHODS

2.1. Acquisition of chemical constituents and targets

To obtain the small molecule chemical constituents of Huai'er (Trametes), the HERB database was searched using the keyword "Huai'er (Trametes)." The TCMSP database was utilized to collect target information for these constituents. Target proteins were annotated and filtered using the Uniprot online platform, focusing on human targets and removing duplicates. The resulting targets were used to construct a "constituent-target" network diagram with Cytoscape.²⁰

For psoriasis-related targets, searches in the GeneCards, OMIM, and DisGeNET databases identified relevant targets, which were then consolidated and filtered for duplicates to form a comprehensive target collection.²¹

2.2. Network construction

Using R programming, target genes of Huai'er (Trametes)'s active components were paired with psoriasis-related target genes to identify key intersection genes. Venn diagrams were then generated based on these intersections. To explore the mechanism of Huai'er (Trametes)'s efficacy in psoriasis, a "Traditional Chinese Medicine Components-Targets-Diseases" network diagram was constructed using Cytoscape (version 3.7.2).²²

2.3. GO and KEGG enrichment analysis

The "ClusterProfiler" package in R was used for GO and KEGG enrichment analysis, applying a significance threshold of P < 0.05. GO analysis covered biological processes (BP), molecular functions (MF), and cellular components (CC), identifying key impacts on cellular functions and signaling pathways. KEGG enrichment analysis of candidate targets was also conducted, with results presented in bubble plots.²³

2.4. Transcriptome analysis of psoriasis

The psoriasis-related transcriptomic dataset GSE54456 was downloaded from the Gene Expression Omnibus (GEO) database. From this dataset, 24 psoriasis lesional skin samples and 24 normal skin samples were randomly selected. The normal samples served as the control group, and the psoriasis samples as the experimental group. Differential analysis was performed using the "limma" package in R, with differentially expressed genes (DEGs) identified based on |log2(FoldChange)| > 0.85 and P-value < 0.05.²⁴

2.5. WGCNA

The median absolute deviation (MAD) was calculated for each gene, and the bottom 50% with the lowest MAD were excluded. Outlier genes and samples were removed using the "goodSamplesGenes" function in the R package "WGCNA." A scale-free co-expression network was then constructed, with a minimum gene dendrogram size of 150 and sensitivity set to 18. Modules with a distance of less than 0.6 were merged, resulting in six final co-expression modules. Pearson correlation tests (P < 0.05) were performed to identify gene modules significantly correlated with psoriasis for further analysis.²⁵

2.6. Molecular docking simulation

The protein structures of b-cell lymphoma 2 (BCL2) (1g5m), c-c motif chemokine ligand 2 (CCL2) (1dom), fibronectin 1 (FN1) (1e8b), interleukin 1 beta (IL1B) (1i1b), matrix metallopeptidase 9 (MMP9) (1l6j), and STAT1 (1yvl) were downloaded from the protein data bank (PDB) database. The 2D structures of the compounds genistein, kaempferol, and rutin were obtained from the PubChem database and converted to 3D structures, using Chem3DUltra 14.0 (CambridgeSoft, Cambridge, MA, USA), with energy minimization performed using the MM2 algorithm. The proteins were dehydrated, and organic molecules were removed using PyMOL software (Schrödinger, New York, NY, USA). Hydrogenation and charge computations were conducted using AutoDockTools 1.5.6 (The Scripps Research Institute, La Jolla, CA, USA), and the proteins and compounds were converted to "pdbqt" files to identify suitable active sites. Molecular docking evaluation and docking energy calculations were performed using Vina 1.1.2 (The Scripps Research Institute, La Jolla, CA, USA).²⁶

2.7. Prediction of pharmacophore models

The 2D structures of genistein and kaempferol compounds were downloaded from the PubChem database, and their chemical structures were saved in structure-data file "(SDF)" format. These files were then uploaded to the PharmMapper server (pharmMapper, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China). The reverse docking server PharmMapper was employed to simulate the molecular-target protein docking of genistein and kaempferol. The target range was set to "human protein targets only," while the remaining parameters were kept at default settings. The candidate target proteins and pharmacophore models for genistein and kaempferol were obtained.²⁷

2.8. Preparation of Huai'er (Trametes) aqueous extract

Huai'er (Trametes) particles, a patented medication of Jiangsu Qidong Gaitianli Pharmaceutical Co., Ltd., Qidong, China, were used to derive the Huai'er (Trametes) aqueous extract for this study. The extract was diluted with phosphate-buffered saline (PBS), vibrated for 30 min, heated in a 60 ℃ water bath for 10 min, and then centrifuged for three 30-s intervals. The solution was purified with a 0.22 μm filter (Millipore, MA, USA) and stored at 4 ℃ for further use.²⁰

2.9. Cell culture and treatment

HACaT immortalized keratinocytes (catalog number: HTX2089) were obtained from Gede Chemicals (China) and cultured in Dulbecco's Modified Eagle Medium (DMEM) (catalog number: 11965092) supplemented with 100 U/mL penicillin, 100 μg/mL streptomycin, and 10% fetal bovine serum (FBS) (Gibco, 16140071, Thermo Fisher Scientific, Waltham, MA, USA) in a 5% CO₂ incubator at 37 ℃.²⁸ Once cells reached 80%-90% confluence, they were passaged at a 1∶3 ratio. After discarding the spent medium, cells were washed with PBS and treated with 0.25% trypsin and 0.53 mM ethylenediaminetetraacetic acid at 37 ℃ for 1-2 min. Digestion was stopped by adding DMEM with 10% FBS, and cells were centrifuged at 4 °C, 1200 rpm for 8-10 min. The supernatant was discarded, fresh medium was added, and cells were resuspended and transferred to a T25 flask.

The psoriasis HaCaT cell model was established by adding the M5 cytokine mixture [interleukin-17A (IL-17A), IL-22, Oncostatin M, IL-1α, and tumor necrosis factor alpha (TNF-α), each at 2.5 ng/mL to the HaCaT culture medium and incubating for 72 h.^29,30 Cytokines were purchased from Thermofisher (Thermo Fisher Scientific, Waltham, MA, USA). For Huai'er (Trametes) treatment, HaCaT cells in the logarithmic growth phase were resuspended in DMEM + 10% FBS with Huai'er (Trametes) at concentrations of 0, 2, 4, 8, and 16 mg/mL. The cell suspension, at approximately 1.0 × 10⁶ cells/mL, was seeded into 6-well plates and cultured for 24, 48, and 72 h.

The study groups included: Control group [DMEM without Huai'er (Trametes) for 24 h], Huai'er (Trametes) group [DMEM with 8 mg/mL Huai'er (Trametes) for 24 h], M5 group [M5-treated cells in DMEM without Huai'er (Trametes) for 24 h], M5+Huai'er (Trametes) group [M5-treated cells in DMEM with 8 mg/mL Huai'er (Trametes) for 24 h], M5 + Huai'er (Trametes) + overexpression-negative control (oe-NC) group [M5-treated cells transfected with oe-NC and cultured in DMEM with 8 mg/mL Huai'er (Trametes) for 24 h], and M5 + Huai'er (Trametes) + oe-STAT1 group [M5-treated cells transfected with oe-STAT1 and cultured in DMEM with 8 mg/mL Huai'er (Trametes) for 24 h].

2.10. Lentiviral transduction

STAT1-overexpressing (oe-STAT1) and control (oe-NC) HaCaT cell lines were generated using lentiviral vectors. Briefly, 293T cells were co-transfected with plasmids carrying firefly luciferase and packaging plasmids (CL-0469, Promega) to produce lentiviruses. HaCaT cells (5 × 10⁵/well in 6-well plates) at 70%-90% confluence were infected with virus (MOI = 10, 5 × 10⁶ TU/mL) in the presence of 5 μg/mL polybrene (Merck, TR-1003, Merck KGaA, Darmstadt, Germany) for 4 h, followed by medium replacement. After 48 h, transduction efficiency was assessed via luciferase activity, and stable clones were selected using 60 μg/mL ampicillin (Sangon Biotech, A100339, Shanghai, China).

For subsequent infections, HaCaT cells (5 × 10⁴ cells/mL) were seeded in 6-well plates and exposed to lentivirus (1 × 10⁸ TU/mL) overnight. Infection efficiency was confirmed by quantitative reverse transcription polymerase chain reaction after 48 h, and successfully transduced cells were used for experiments.³¹

2.11. Evaluation of cell viability using cell counting kit-8 (CCK-8) assay

Cells from each group were digested, resuspended, and adjusted to 1 × 10⁵ cells/mL; 100 μL per well were seeded in 96-well plates and incubated overnight. Cell viability was assessed at 12, 24, 36, and 48 h using a CCK-8 kit (C0041, Beyotime, Shanghai, China) according to the manufacturer’s protocol. Briefly, 10 μL of CCK-8 reagent was added per well and incubated for 2 h at 37 ℃. Absorbance was then measured at 450 nm using an ELISA reader.^32,33

2.12. EdU staining assay

Cells (1 × 10⁵/well) were seeded in 24-well plates and cultured in triplicate. Proliferation was evaluated using 10 μmol/L EdU (ST067, Beyotime, Shanghai, China) for 2 h. Cells were fixed in 4% paraformaldehyde (15 min), washed with PBS containing 3% bovine serum albumin, and permeabilized with 0.5% Triton X-100 (20 min). Nuclei were counterstained with 4′,6-diamidino-2-phenylindole (DAPI) (C1002, Beyotime, Shanghai, China) for 5 min. Fluorescence images (6-10 random fields) were acquired using an FM-600 fluorescence microscope (Shanghai Precision Instrument Co., Ltd., Shanghai, China), and EdU-positive cells were quantified. Each experiment was repeated three times.³⁴

2.13. Scratch experiment

A scratch experiment was conducted by drawing evenly spaced lines on the bottom of a 6-well plate. Cells were seeded and grown to 100% confluency. A scratch was made using a 200 μL pipette tip, and the medium was replaced with a serum-free culture medium. The distance between the scratches was measured under an optical microscope (Leica, Model: DM500, Leica Microsystems, Wetzlar, Germany) at 0 and 24 h. Images were captured using an inverted microscope to observe the migration. The scratch area was analyzed using Image-Pro Plus 6.0 software (Media Cybernetics, Rockville, MD, USA), and the wound healing rate was calculated as a percentage of wound closure.^35,36

2.14. Western blot

Total protein was extracted using a commercial kit (BB3101, Bestbio, Shanghai, China) and quantified with a bicinchoninic acid assay (P0012S, Beyotime Biotechnology, Shanghai, China). Equal amounts of protein (50 μg) were separated on 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels and transferred to polyvinylidene difluoride membranes (IPVH00010, Merck) at 250 mA for 90 min. Membranes were blocked in 5% skim milk/ Tris-Buffered Saline with Tween-20 for 2 h, then incubated overnight at 4 ℃ with primary antibodies (Supplementary Table 1). After washing, membranes were incubated with horseradish peroxidase-conjugated goat anti-rabbit immunoglobulin G (1∶2000, ab6721, Abcam, Cambridge, UK) or goat anti-mouse IgG (1∶2000, Abcam, Cambridge, ab6789, UK) for 1 h at room temperature. Bands were visualized using ECL reagent (P0018FS, Beyotime Biotechnology, Shanghai, China) and imaged in a dark box.³⁷ Each experiment was repeated three times.

2.15. Reverse transcription quantitative polymerase chain reaction (RT-qPCR)

Total RNA was extracted from the samples using Trizol (Thermo Fisher Scientific, Waltham, MA, 16096020, USA). cDNA was synthesized by reverse transcription using the reverse transcription kit (Takara, RR047A, Japan). The reaction mixture was prepared using the One Step TB Green® PrimeScript™ RT-PCR Kit (Takara Bio Inc., Shiga, RR066A, Japan), and the samples underwent RT-qPCR on the real-time fluorescence quantitative PCR instrument (Thermo Fisher Scientific, Waltham, MA, ABI 7500, USA). Glyceraldehyde-3-phosphate dehydrogenase was chosen as the housekeeping gene. All RT-qPCR assays were performed in triplicate. The primer sequences are shown in Supplementary Table 2. The 2^-ΔΔCt method was used to determine the fold change in gene expression between the experimental and control groups.³⁸

2.16. Construction of mouse model of psoriasis

Forty 8-week-old male Balb/c mice (catalog number: 213, 20-25 g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd in Beijing, China. The mice were kept in standard cages, maintained at a constant room temperature of (23 ± 1) ℃, and subjected to a 12-h light/dark cycle with ad libitum access to food and water. Prior to the experiment, the mice underwent one week of acclimatization. The experimental procedures and animal use protocol were approved by Hunan Children's Hospital.

Each day, 5% imiquimod cream (50 mg, Aldara,3M Health Care Ltd., Loughborough, UK) was evenly applied to the ears of the mice at scheduled times (Supplementary Figure 1).³⁹ Six hours after the application, the Huai'er (Trametes) treatment group received a daily oral gavage of 4 g/kg Huai'er (Trametes), while the control group received no treatment. On the 8th day, the mice were euthanized, and skin samples were collected for hematoxylin and eosin (HE) staining and RNA extraction.³⁰

To create STAT1-overexpressing mice, a lentivirus was packaged with the core plasmid pLL3.7-Fgf2 and auxiliary plasmids (psPAX2, pMD2.G) using services provided by Shenggong Biotechnology (Shanghai, China). The control group received the same dose of an empty lentiviral vector. The viral concentration used was 5 × 10⁶ TU/mL, and the mice were injected every two days from the start to the end of the experiment.^40,41

The experimental groups included: Normal (no treatment), psoriasis (treated with only 5% imiquimod cream), psoriasis + Huai'er (Trametes) (5% imiquimod cream followed by 4g/kg Huai'er (Trametes)), psoriasis + Huai'er (Trametes) + PBS (5% imiquimod cream followed by Huai'er (Trametes) and PBS injection), and psoriasis + Huai'er (Trametes) + rSTAT1 (5% imiquimod cream followed by Huai'er (Trametes) and STAT1-overexpressing lentivirus). Daily observations and photographs of ear lesions were taken, and severity was assessed using the Psoriasis Area and Severity Index scoring system, with scores assigned to erythema and scaling on a scale of 0 to 4.³⁰

All animal experiments were approved by the Animal Ethics Committee of Hunan Children's Hospital.

2.17. Immunohistochemical staining

Paraffin-embedded mouse skin sections were baked at 60 ℃ for 20 min, dewaxed in xylene (2 × 15 min), and rehydrated through graded ethanol (100%, 95%, 70%). Endogenous peroxidase was blocked with 3% H₂O₂ for 10 min. Antigen retrieval was performed in citrate buffer via microwave heating (3 min), followed by cooling and PBS washing. Sections were blocked with normal goat serum (E510009, Sangon Biotech, Shanghai, China) for 20 min at room temperature.

Primary antibodies against keratin 6 (KRT6) (MA5-12429, 1∶200, Thermo Fisher Scientific, Waltham, MA, USA) or KRT1 (ab185628, 1∶600, Abcam, Cambridge, UK) were incubated overnight at 4 ℃. After PBS washing, goat anti-mouse IgG secondary antibody (A-21135, 1∶200, Thermo Fisher Scientific, Waltham, MA, USA) was applied for 30 min. 3,3′-diaminobenzidine (DAB) substrate (DAB150, Sigma-Aldrich, St. Louis, MO, USA) was used for 6 min, followed by hematoxylin counterstaining (30 s), dehydration, and xylene clearing. Slides were mounted with neutral resin and observed under a BX63 light microscope (Olympus Corporation, Tokyo, Japan). Protein expression was quantified using the Aperio Scanscope system.⁴²

2.18. HE staining

Mouse skin tissues were fixed in 4% paraformaldehyde, embedded in paraffin, sectioned, and stained using HE. After deparaffinization and rehydration, sections were stained with hematoxylin for 5-10 min, rinsed, then stained with eosin for 5-10 min, followed by dehydration, clearing, and mounting.⁴³ Infiltrating cells in the dermis were quantified in five random areas per sample.

2.19. ELISA detection of inflammatory factors

Commercial kits (IL-6, catalog number: KMC0062; TNF-α, catalog number: BMS607-3; IL-17, catalog number: BMS6001; IL-23, catalog number: BMS6017) purchased from Thermofisher (Thermo Fisher Scientific, Waltham, MA, USA) were used to measure the levels of inflammatory factors in serum samples following the manufacturer's instructions.³⁰

2.20. Statistical analysis

The software and versions utilized in this research are as follows: R software version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria), RStudio (RStudio, PBC, Boston, MA, USA) integrated development environment version 4.2.1, Perl language version 5.30.0 (he Perl Foundation, Walnut, CA, USA), Cytoscape version 3.7.2 (Cytoscape Consortium, San Diego, CA, USA), and Graphpad Prism 8.0 (GraphPad Software, San Diego, CA, USA). The quantitative data are presented as mean ± standard deviation and independent sample t-tests were conducted for intergroup comparisons. Repeated measures analysis of variance was used to compare the data among different time points, followed by post-hoc tests using Bonferroni correction. A significance level of P < 0.05 was considered statistically significant.

3. RESULTS

3.1. Huai'er (Trametes) extract inhibits proliferation, migration, and inflammatory factor expression of psoriasis keratinocytes

To assess the effects of Huai'er (Trametes) on keratinocytes, HaCaT cells were treated with varying concentrations of Huai'er (Trametes) extract (0-16 mg/mL) for 24-72 h. CCK-8 assays showed that cell viability decreased in a time- and dose-dependent manner, with maximal inhibition at 8 mg/mL (Figures 1A, 1B). Using this concentration, EdU assays further demonstrated that Huai'er (Trametes) markedly suppressed HaCaT proliferation over time (Figures 1C, 1D). Scratch experiments indicated significantly reduced migration in the Huai'er (Trametes) group compared with controls after 24 h (Figure 2A).

A: bright-field/phase-contrast image of HaCaT cells without staining. Scale bar = 50 μm; B: CCK-8 cell viability of HaCaT cells treated with Huai'er (*Trametes*) at 0, 2, 4, 8, and 16 mg/mL for 24, 48, and 72 h. Two-way ANOVA (factors: concentration and time) was performed with post-hoc tests when appropriate; C: EdU fluorescence staining of HaCaT cells treated with 8 mg/mL Huai'er (*Trametes*) for different time points.C1: 0 h; C2: 12 h; C3: 24 h; C4: 48 h. EdU⁺ cells are shown in red; nuclei are stained with DAPI (blue). Scale bar = 50 μm.); D: percentage of EdU⁺ cells in different time groups (0, 12, 24, 48 h). AEdU: 5-ethynyl-2′-deoxyuridine; DAPI: 4′, 6-diamidino-2-phenylindole; CCK-8: cell counting kit-8; ANOVA: analysis of variance. Data are presented as mean ± standard deviation (*n =* 3). One-way ANOVA was used for statistical analysis. Compared with the 0 h group, ^aP < 0.01.

A: scratch-wound assay of HaCaT cells imaged by phase-contrast microscopy (no staining); a 100 μm scale bar is shown at the bottom right of each image. A1-A4: representative images of Control and Huai'er (*Trametes*) at 0 h and 24 h (A1: Control group at 0 h; A2: Huai’er (Trametes) group at 0 h; A3: Control group at 24 h; A4: Huai’er (Trametes) group at 24 h); A5: quantification of migration distance (%); B: RT-qPCR analysis of inflammatory cytokine mRNA levels. B1: IL-6; B2: IL-8; B3: IL-10; B4: IL-23; B5: IL-17; B6: TNF-α. The cell experiments mentioned above were repeated three times. Control: untreated; Huai'er (*Trametes*): treated with Huai'er (*Trametes*) at 8 mg/mL for 24 h; scratch assay time points: 0 h and 24 h. RT-qPCR: reverse transcription quantitative polymerase chain reaction; IL: interleukin; TNF-α: tumor necrosis factor alpha; ANOVA: analysis of variance. Data are presented as mean ± standard deviation (n = 3). Two-group comparisons used a two-tailed unpaired t-test (or one-way ANOVA with post-hoc tests, keep consistent with your methods). Compared to the Control group, ^aP < 0.01.

Furthermore, we investigated the regulatory effect of Huai'er (Trametes) on inflammatory factors in HaCaT cells. RT-qPCR and ELISA analyses revealed that Huai'er (Trametes) significantly downregulated the mRNA and protein expression of inflammatory cytokines, including IL-6, IL-8, IL-10, IL-23, IL-17, and TNF-α (Figure 2B).

These results suggest that Huai'er (Trametes) can inhibit the proliferation and migration of HaCaT cells while reducing the expression levels of inflammatory factors.

3.2. Exploring the potential molecular mechanisms and target identification of Huai'er (Trametes) in treating psoriasis

To identify potential targets of Huai'er (Trametes) in treating psoriasis and further elucidate its specific molecular mechanisms, we conducted an investigation using network pharmacology methods (Supplementary Figure 2). Initially, we searched the HERB database for "Huai'er (Trametes)" to acquire its active small-molecule compounds, which included genistein, glucuronic acid, kaempferol, and rutin (Supplementary Table 3). Subsequently, we retrieved the corresponding targets of these active compounds from the TCMSP database and identified and annotated these targets using the Uniprot online website, resulting in a total of 146 modulated genes (Figure 3A). Additionally, we collected psoriasis-related targets from the OMIM, GeneCard, and Disdenet databases, yielding 4866 targets after removing duplicates (Figure 3B). By intersecting these targets with Huai'er (Trametes)'s modulated targets, we obtained 101 potential targets for the treatment of psoriasis by Huai'er (Trametes) (Figure 3C). Next, we imported these active compounds and intersected targets into Cytoscape to construct a network of Huai'er (Trametes)'s involvement in psoriasis treatment, consisting of ingredients, targets, and diseases (Figure 3D).

A: network of Huai'er (Trametes)-derived small-molecule compounds and their putative target genes (node size proportional to degree); B: venn diagram of psoriasis-related genes retrieved from GeneCards, OMIM, and DisGeNET, showing the intersection of the three databases; C: venn diagram showing the overlap between disease-related targets (psoriasis) and drug-related targets (Huai'er (Trametes)); D: Huai'er (Trametes)-active ingredient-target-disease network built in Cytoscape: blue = Huai'er (Trametes); yellow = psoriasis; red = active ingredients (rutin, genistein, kaempferol, glucuronic acid); green = potential therapeutic targets; Groups: Disease targets were obtained by querying “psoriasis” in GeneCards, OMIM, and DisGeNET and then de-duplicated; drug targets were compiled for Huai'er (Trametes) active ingredients from literature/databases. Panels B-C display set intersections, and panel D visualizes ingredient-target-disease associations; GeneCards, human gene database; OMIM: online mendelian inheritance in man; DisGeNET: disease-gene association database; PPI: protein-protein interaction (if applicable).

To uncover potential molecular mechanisms or pathways involved in the treatment of psoriasis by Huai'er (Trametes), we performed enrichment analysis on these 101 potential targets. The results showed that these targets were mainly enriched in biological processes such as response to oxidative stress, gland development, and epithelial cell proliferation (Figure 4A). The enriched CC included membrane microdomains, vesicle lumen, and membrane rafts (Figure 4B). In terms of MF, the enrichment was primarily related to protein serine/threonine/tyrosine kinase activity, protein serine/threonine kinase activity, and protein serine kinase activity (Figure 4C). The enriched KEGG pathways predominantly included the PI3K-Akt signaling pathway, Th17 cell differentiation, and the IL-17 signaling pathway (Figure 4D). These results suggest that Huai'er (Trametes) may potentially treat psoriasis by involving pathways related to oxidative stress, cell proliferation, and immune cell regulation. Subsequently, we obtained the protein-protein interaction relationships of these 101 potential modulated genes from the STRING online database and visualized them using Cytoscape software (Figure 4E). Additionally, we calculated the gene connectivity using R software to identify the top 30 genes with the highest number of connections (Figure 4F).

A: enrichment results of 101 potential therapeutic targets in GO-BP; B: enrichment results of 101 potential therapeutic targets in GO-CC; C: enrichment results of 101 potential therapeutic targets in GO-MF; D: enrichment results of 101 potential therapeutic targets in KEGG; E: protein interaction network of 101 potential therapeutic targets based on the STRING online database, constructed using Cytoscape software. The size of the circles represents the number of gene connection nodes, with larger circles indicating more connections; F: bar graph showing the number of gene connection nodes for the top 30 ranked potential therapeutic targets. GO: Gene Ontology; BP: biological process; CC: cellular component; MF: molecular function; KEGG: Kyoto Encyclopedia of Genes and Genomes; STRING: Search Tool for the Retrieval of Interacting Genes/Proteins; PPI: protein-protein interaction; FDR: false discovery rate. Enrichment was computed with a hypergeometric test and Benjamini-Hochberg FDR correction.

In conclusion, we have identified 101 potential targets for Huai'er (Trametes) in treating psoriasis, and its therapeutic mechanism may be related to pathways involving oxidative stress, cell proliferation, and immune cell regulation.

3.3. Gene screening and discovery of core therapeutic targets in psoriasis

To identify the core genes associated with the treatment of psoriasis using Huai'er (Trametes), we employed the WGCNA analysis method to screen for psoriasis-related genes and unravel the specific molecular mechanisms underlying the occurrence and development of psoriasis. Transcriptional sequencing datasets of 24 normal skin samples and 24 psoriasis skin samples were randomly selected from the psoriasis-related microarray GEO dataset GSE54456 (GSE54456) obtained from the GEO database. Using the WGCNA analysis, a co-expression network of all genes was constructed. The soft threshold β of the chip was computed using R software, and the optimal β value satisfying the scale-free network law was found to be 18 (Supplementary Figure 3A). Based on this soft threshold, we set the minimum module size to 150 and the module merging threshold to 0.6 and performed a dynamic tree cut (Supplementary Figure 3B). The clustering dendrogram, shown in Figure 3B, identified a total of six gene modules, namely MEgrey60, MEgreen, MEcyan, MElightcyan, MElightyellow, and MEgrey modules. Using these six clustering modules, we classified normal skin and psoriasis skin according to clinical traits and further analyzed the correlation between gene modules and clinical traits. The results revealed that MEgrey60 was positively correlated with psoriasis, with a correlation coefficient of 0.7, while MElightcyan was negatively correlated with psoriasis, with a correlation coefficient of －0.88. Moreover, the correlation P-values of both modules were found to be less than 0.05 (Supplementary Figure 3C).

To further identify genes related to psoriasis, we performed a differential analysis of gene expression between normal skin and psoriasis skin using the "limma" package in R software. The results showed that in psoriasis skin, 1019 genes were significantly upregulated, while 923 genes were significantly downregulated (Supplementary Figure 3D). We also analyzed these DEGs in relation to disease-related module genes and found that the MEgrey60 module had 866 intersected DEGs related to psoriasis, while the MElightcyan module had 846 intersected DEGs (Supplementary Figure 3E). Subsequently, we obtained psoriasis-related genes from the GeneCard online database and Disgenet online database and further analyzed them with the DEGs in the disease-related modules. The results revealed that the MEgrey60 module contained 143 DEGs related to psoriasis (Supplementary Figure 4A). The GO enrichment analysis showed that these genes were mainly enriched in biological processes such as cytokine-mediated signaling pathways, cell chemotaxis, and leukocyte migration (Supplementary Figure 4B). In addition, the KEGG enrichment analysis indicated their significant roles in pathways such as cytokine-cytokine receptor interaction, IL-17 signaling pathway, and chemokine signaling pathway (Supplementary Figure 4C). In the MElightcyan module, we obtained 59 P-DEGs (Supplementary Figure 4D). The GO enrichment analysis showed that these genes were mainly enriched in biological processes such as epithelial cell proliferation, urogenital system development, and leukocyte migration, as well as signaling pathways, including proteoglycans in cancer and AGE-RAGE signaling pathway in diabetic complications (supplementary Figures 4E, 4F). These pathways were closely associated with inflammation and immune processes, which are major factors contributing to psoriasis. Particularly, the IL-17 signaling pathway played a key role in the pathogenesis of psoriasis, further validating the accuracy of our analysis results. In summary, through WGCNA and differential expression analysis, we identified 202 genes closely associated with psoriasis.

Furthermore, we conducted an intersection analysis between the top 30 core therapeutic targets obtained from network pharmacology analysis and the psoriasis-related genes identified by WGCNA. The results revealed 6 core therapeutic targets: BCL2, IL1B, FN1, MMP9, CCL2, and STAT1 (Supplementary Figure 4G). Visualization analysis of transcriptomic sequencing data showed that compared to the normal group, BCL2 and FN1 were expressed at lower levels in the psoriasis group, while CCL2, IL1B, MMP9, and STAT1 were expressed at higher levels in the psoriasis group (Supplementary Figure 4H).

Based on these findings, our combination of WGCNA and network pharmacology analysis identified 6 potential core therapeutic targets, providing a new direction for Huai'er (Trametes)'s treatment of psoriasis.

3.4. Molecular docking analysis of key Huai'er (Trametes) targets and pharmacophores

To screen key targets of Huai'er (Trametes) in psoriasis, molecular docking and pharmacophore modeling were performed on six core targets. According to TCMSP predictions, genistein potentially regulates all six targets, kaempferol regulates BCL2 and STAT1, and rutin regulates IL1B. Using AutoDockTools 1.5.6 and Vina 1.1.2, we docked compounds with their predicted proteins (three repetitions each), evaluating average binding free energy (binding energy < 0 kcal/mol indicates spontaneous binding). Docking results demonstrated strong interactions, with the top binding affinities observed for genistein-MMP9 (－10.0 kcal/mol), kaempferol-STAT1 (－8.1 kcal/mol), and genistein-STAT1 (－8.0 kcal/mol) (Supplementary Figure 5A).

Pharmacophore prediction via PharmMapper showed that genistein contained hydrophobic, donor, acceptor, and positive groups capable of binding STAT1 (1 Hydrophobic, 1 Positive, 2 Donor, 4 Acceptor) and MMP9 (1 Hydrophobic, 2 Donor, 4 Acceptor). Kaempferol featured similar interaction groups for STAT1 (1 Hydrophobic, 1 Positive, 2 Donor, 4 Acceptor) (Supplementary Figure 5B).

Based on the above results, as well as the OB and DL values of genistein and kaempferol in Supplementary Table 3, we hypothesized that STAT1 is Huai'er (Trametes)'s key therapeutic target in the treatment of psoriasis.

3.5. Huai'er (Trametes) maintains the homeostasis of psoriasis keratinocytes by modulating STAT1

Bioinformatics analysis suggested STAT1 as a core target of Huai'er (Trametes) in psoriasis. STAT1, a key transcription factor of the STAT family, activates through dimerization and nuclear translocation to regulate genes involved in immunity, cell proliferation, and apoptosis.

To explore whether Huai'er (Trametes) regulates psoriatic keratinocyte homeostasis via STAT1, we first established an in vitro psoriasis model by stimulating HaCaT cells with M5 cytokine cocktail (IL-17A, IL-22, TNF-α, IL-1α, and Oncostatin M) (Supplementary Figure 6A). After 72 h of M5 treatment, CCK-8 assays showed significantly increased cell viability (Supplementary Figure 6B), and RT-qPCR and Western blot indicated elevated expression of hyperproliferation markers KRT6 and KRT1 (supplementary Figures 6C-6E). Moreover, the levels of inflammatory cytokines (IL-6, IL-8, IL-10, IL-23, IL-17, and TNF-α) were markedly upregulated (supplementary Figures 6F, 6G), confirming successful induction of a psoriatic keratinocyte phenotype.

These results demonstrate the successful establishment of a psoriasis keratinocyte model through M5 stimulation of HaCaT cells, allowing for in vitro investigation of psoriasis keratinocytes.

3.6. Huai'er (Trametes) attenuates excessive proliferation and expression of inflammatory factors in psoriasis HaCaT by suppressing STAT1

STAT1 activation depends on phosphorylation ⁴⁴, which drives its nuclear translocation and transcriptional activity. To investigate whether Huai'er (Trametes) modulates psoriatic keratinocytes through STAT1, we treated M5-induced HaCaT cells with Huai'er (Trametes) and manipulated STAT1 expression via lentiviral transduction. Western blot results showed that STAT1 and p-STAT1 levels were markedly elevated in the M5 group versus Control, indicating STAT1 activation. Huai'er (Trametes) treatment significantly reduced both total and phosphorylated STAT1, whereas oe-STAT1 reversed this effect (supplementary Figures 7A-7C). Functionally, M5 stimulation enhanced cell viability (CCK8), proliferation (EdU), and migration (scratch assay), all of which were diminished by Huai'er (Trametes). These inhibitory effects were abolished upon STAT1 overexpression (supplementary Figures 7D-7H). Similarly, Huai'er (Trametes) downregulated inflammatory cytokine expression at both mRNA and protein levels, while oe-STAT1 restored inflammatory factor expression (supplementary Figures 7I-7J).

These findings indicate that STAT1 is highly expressed in psoriasis HaCaT, and Huai'er (Trametes) attenuates excessive proliferation and expression of inflammatory factors in psoriasis HaCaT by suppressing STAT1 expression.

3.7. Huai'er (Trametes) alleviates IMQ-induced psoriasis-like lesions in mice by inhibiting STAT1 activation

To assess Huai'er (Trametes)’s therapeutic potential in vivo, IMQ-induced psoriasis-like mouse models were treated orally with Huai'er (Trametes). Compared with the Normal group, IMQ-treated mice displayed pronounced erythema and scaling, which were markedly improved in the psoriasis + Huai'er (Trametes) group. STAT1 overexpression (psoriasis + Huai'er (Trametes) + rSTAT1) reversed this improvement, resulting in aggravated skin lesions (Supplementary Figure 8A). Consistently, erythema and scaling scores on day 7 were significantly reduced by Huai'er (Trametes) treatment but increased again upon rSTAT1 administration (supplementary Figures 8B-8C). Immunohistochemistry, qPCR, and Western blot analyses showed increased STAT1/p-STAT1, KRT6, and KRT1 expression in psoriatic mice vs Normal controls, all of which were downregulated by Huai'er (Trametes). STAT1 overexpression restored their expression levels (supplementary Figures 8D-8H). HE staining demonstrated that Huai'er (Trametes) reduced inflammatory cell infiltration in skin lesions, an effect negated by rSTAT1 (supplementary Figures 8I-8J). Similarly, serum cytokine levels were decreased by Huai'er (Trametes) but re-elevated by rSTAT1 (Supplementary Figure 8K).

In conclusion, Huai'er (Trametes) can effectively improve IMQ-induced mouse psoriasis-like skin lesions by suppressing STAT1 expression and activation.

4. DISCUSSION

Psoriasis is a complex autoimmune skin disease with an unclear pathogenesis.^45-47 This study applied network pharmacology and transcriptomics to reveal the potential targets and molecular mechanisms of Huai'er (Trametes) in treating psoriasis. The results demonstrated that Huai'er (Trametes) significantly alleviates psoriasis-like symptoms, including excessive keratinocyte proliferation and migration as well as overexpression of inflammatory factors. These findings validate Huai'er (Trametes)'s therapeutic potential and align with its known anti-tumor properties, extending its application to chronic inflammatory skin diseases.

Through molecular docking and pharmacophore modeling, STAT1 was identified as the core therapeutic target of Huai'er (Trametes) in psoriasis.^48-50 STAT1 is significantly overexpressed in psoriasis and plays a critical role in inflammatory cytokine secretion and abnormal keratinocyte behavior. Huai'er (Trametes) suppressed STAT1 expression and phosphorylation, mitigating excessive proliferation and inflammatory responses in psoriasis.⁵¹ This finding underscores the central role of STAT1 in psoriasis and provides experimental evidence for targeting STAT1 in therapy.^52-54

Enrichment analysis of Huai'er (Trametes)'s targets and psoriasis-related genes suggests that Huai'er (Trametes) exerts therapeutic effects through pathways related to oxidative stress, cell proliferation, and immune cell regulation.^55,56 Notably, the IL-17 signaling pathway emerged as a key mechanism of action. These findings align with prevailing hypotheses on psoriasis pathogenesis, further corroborating the reliability of this study.

Compared with traditional experimental methods, this study leveraged network pharmacology and transcriptomics to systematically identify Huai'er (Trametes)’s active compounds and therapeutic targets.^57-59 Utilizing the HERB and TCMSP databases, active compounds and targets of Huai'er (Trametes) were identified, and WGCNA analysis further confirmed its potential therapeutic targets for psoriasis.^60-62 This integrative approach provided a novel perspective for understanding Huai'er (Trametes)'s mechanisms of action.

While this study sheds light on the potential mechanisms of Huai'er (Trametes) in psoriasis, it has several limitations. First, although multiple databases and analysis methods were employed, the findings lack validation from clinical patient data. Second, the study primarily relied on in vitro cell models and animal models, requiring further large-scale clinical verification. Additionally, the predictive accuracy of molecular docking and pharmacophore models requires optimization. Future studies should validate Huai'er (Trametes)’s therapeutic effects in animal and clinical settings, explore its synergistic use with other therapies, and assess its toxicity and safety profile to provide a more robust basis for clinical application.

Given the central role of STAT1 in psoriasis and its significant modulation by Huai'er (Trametes), this study offers insights into developing STAT1-targeted therapies.^63-65 Additionally, by elucidating Huai'er (Trametes)’s role in immune regulation and key signaling pathways, this research highlights its potential for personalized treatment of psoriasis. Huai'er (Trametes) may serve as a promising therapeutic option for patients with high STAT1 expression, providing a tailored and targeted approach to treatment.

In conclusion, this study demonstrates that Huai'er (Trametes) alleviates psoriasis by suppressing keratinocyte proliferation, migration, and inflammatory cytokine production via inhibition of STAT1. Integrated analyses identified STAT1 as a core therapeutic target, linking Huai'er (Trametes)’s efficacy to immune modulation and IL-17-related signaling. These findings provide mechanistic insight into Huai'er (Trametes)’s anti-psoriatic activity and support its clinical potential. Nonetheless, further validation in clinical settings and safety assessments are needed. This work lays a foundation for developing STAT1-targeted therapies for psoriasis.

5. SUPPORTING INFORMATION

Supporting data to this article can be found online at http://www.journaltcm.com.

JTCM-45-6-1317-s1.pdf^{(1.9MB, pdf)}

Contributor Information

Litao ZHANG, Email: zhanglitao@medmail.com.cn.

Zhu WEI, Email: 34438881@qq.com.

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Associated Data

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Supplementary Materials

Supporting data to this article can be found online at http://www.journaltcm.com.

JTCM-45-6-1317-s1.pdf^{(1.9MB, pdf)}

[b1] 1. Nogueira S, Rodrigues MA, Vender R, Torres T. . Tapinarof for the treatment of psoriasis. Dermatol Ther 2022; 35: e15931. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b2] 2. Bonelli M, Kerschbaumer A, Kastrati K, et al. Selectivity, efficacy and safety of JAKinibs: new evidence for a still evolving story. Ann Rheum Dis 2024; 83: 139-60. [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Psoriasis intervention by Huai’er (Trametes): unveiling novel targets via network pharmacology

Keyao LI

Ye SHU

Jing CHANG

Jianping TANG

Litao ZHANG

Zhu WEI

Abstract

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

1. INTRODUCTION

2. MATERIALS AND METHODS

2.1. Acquisition of chemical constituents and targets

2.2. Network construction

2.3. GO and KEGG enrichment analysis

2.4. Transcriptome analysis of psoriasis

2.5. WGCNA

2.6. Molecular docking simulation

2.7. Prediction of pharmacophore models

2.8. Preparation of Huai'er (Trametes) aqueous extract

2.9. Cell culture and treatment

2.10. Lentiviral transduction

2.11. Evaluation of cell viability using cell counting kit-8 (CCK-8) assay

2.12. EdU staining assay

2.13. Scratch experiment

2.14. Western blot

2.15. Reverse transcription quantitative polymerase chain reaction (RT-qPCR)

2.16. Construction of mouse model of psoriasis

2.17. Immunohistochemical staining

2.18. HE staining

2.19. ELISA detection of inflammatory factors

2.20. Statistical analysis

3. RESULTS

3.1. Huai'er (Trametes) extract inhibits proliferation, migration, and inflammatory factor expression of psoriasis keratinocytes

Figure 1. Investigation of the effects of Huai'er (Trametes) on HaCaT cell behavior.

Figure 2. Investigation of the effects of Huai'er (Trametes) on HaCaT cell behavior and expression of inflammatory factors.

3.2. Exploring the potential molecular mechanisms and target identification of Huai'er (Trametes) in treating psoriasis

Figure 3. Network pharmacology investigation of potential targets and mechanisms of Huai'er (Trametes) in treating psoriasis.

Figure 4. Network pharmacology investigation of potential targets and mechanisms of Huai'er (Trametes) in treating psoriasis.

3.3. Gene screening and discovery of core therapeutic targets in psoriasis

3.4. Molecular docking analysis of key Huai'er (Trametes) targets and pharmacophores

3.5. Huai'er (Trametes) maintains the homeostasis of psoriasis keratinocytes by modulating STAT1

3.6. Huai'er (Trametes) attenuates excessive proliferation and expression of inflammatory factors in psoriasis HaCaT by suppressing STAT1

3.7. Huai'er (Trametes) alleviates IMQ-induced psoriasis-like lesions in mice by inhibiting STAT1 activation

4. DISCUSSION

5. SUPPORTING INFORMATION

Contributor Information

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

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