Network Toxicology and Molecular Docking Reveal Diethyl Phthalate as a Potential Epigenetic Modulator in Psoriasis Pathogenesis

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Psoriasis, a chronic inflammatory skin disease, is characterized by immune dysregulation and epigenetic alterations. However, the potential contribution of DEP to psoriasis pathogenesis remains poorly understood. This study employed a network toxicology approach, integrating protein-protein interaction (PPI) network analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and molecular docking to systematically evaluate the potential role of DEP in psoriasis. A total of 47 intersecting genes were identified between DEP targets and psoriasis-related genes. Key hub genes, including SIRT1, HDAC1, BRD4, EP300, and EZH2, were identified, highlighting their possible involvement in DEP-mediated toxicity. Enrichment analysis revealed significant associations with apoptosis, chromatin remodeling, and immune regulation. Molecular docking results demonstrated strong binding affinities between DEP and core proteins, particularly SIRT1. These findings suggest that DEP may exacerbate psoriasis through epigenetic modulation and immune dysregulation. This study provides a novel mechanistic link between environmental exposure and inflammatory skin disease and underscores the need for further experimental validation. Diethyl phthalate (DEP) Psoriasis Network toxicology Molecular docking Epigenetic regulation Figures Figure 1 Figure 2 Figure 3 1. Introduction Diethyl phthalate (DEP), a widely used phthalate ester, is commonly found in industrial and consumer products, including plastics, cosmetics, personal care products, and pharmaceuticals[ 1 ]. Due to its extensive use and environmental persistence, DEP has been detected in air, water, soil, and human biological samples, indicating widespread human exposure through ingestion, inhalation, and dermal absorption[ 2 ]. Notably, dermal exposure constitutes a significant yet often overlooked route of DEP absorption, particularly for individuals frequently using personal care products such as perfumes, lotions, and sunscreens, where DEP serves as a solvent and penetration enhancer[ 3 , 4 ]. Given its lipophilic properties, DEP can readily penetrate the stratum corneum, facilitating systemic absorption and increasing the risk of bioaccumulation [ 5 ]. The skin acts as a primary barrier against environmental toxins, but in individuals with psoriasis and compromised skin barrier function, increased permeability to environmental pollutants has been observed[ 6 ]. These conditions are characterized by defects in filaggrin, tight junctions, and lipid composition, which disrupt epidermal integrity and facilitate the transdermal absorption of harmful chemicals, including DEP [ 7 ]. DEP accumulation in the skin and systemic circulation raises concerns regarding its potential impact on immune homeostasis and inflammatory responses [ 8 ]. Despite these concerns, the specific molecular mechanisms by which DEP contributes to psoriasis remain unclear, necessitating further investigation. Psoriasis are chronic inflammatory skin diseases influenced by genetic predisposition, immune dysregulation, and environmental factors[ 9 ]. Although genome-wide association studies (GWAS) have identified multiple susceptibility loci, growing evidence suggests that environmental pollutants can serve as disease triggers through epigenetic modifications [ 9 ]. Epigenetic alterations, including DNA methylation, histone modifications, and non-coding RNA regulation, modulate gene expression without altering the genetic sequence [ 10 ]. In psoriasis, histone modifications are associated with sustained inflammatory responses and keratinocyte hyperproliferation[ 11 , 12 ]. Importantly, reversing these epigenetic modifications has been shown to mitigate disease severity, highlighting epigenetic pathways as potential therapeutic targets [ 13 ]. Given that DEP has been implicated in disrupting endocrine and immune signaling pathways [ 14 ], it is plausible that DEP exposure contributes to psoriasis through epigenetic and transcriptional dysregulation. However, a systematic investigation into these molecular mechanisms remains lacking. Previous studies on DEP toxicity have primarily focused on its reproductive and metabolic effects, while its impact on dermatological conditions remains poorly understood [ 15 ]. Although some evidence suggests that DEP may modulate immune responses and inflammatory signaling, its direct role in inflammatory skin diseases such as psoriasis remains uncharacterized [ 16 ]. DEP may contribute to their exacerbation via epigenetic modifications, chromatin remodeling, and transcriptional regulation. To bridge this knowledge gap, the present study systematically investigates the molecular mechanisms through which DEP may contribute to psoriasis pathogenesis. By integrating network toxicology, protein-protein interaction (PPI) analysis, functional enrichment analysis (GO and KEGG), and molecular docking, we explore potential interactions between DEP and key genes associated with psoriasis. This study provides the first comprehensive investigation into the molecular mechanisms linking DEP exposure to psoriasis, offering novel insights into the dermatotoxic potential of DEP as an environmental pollutant. A deeper understanding of these interactions may contribute to the development of targeted therapeutic strategies and enhance efforts to mitigate the impact of environmental pollutants on skin health. 2. Methods 2.1. Network Toxicological Analysis of DEP The standard SMILES format for the active ingredient Diethyl Phthalate (DEP) was obtained from the PubChem platform ( https://pubchem.ncbi.nlm.nih.gov/ ). This sequence was then imported into ADMETlab 2.0 ( https://admetmesh.scbdd.com/ ) and ProTox-II ( https://comptox.charite.de/protox3/ ) software tools for comprehensive toxicity analysis. These platforms provided predictions regarding the toxicological properties of DEP, including potential effects on various biological systems. 2.2. Collection of DEP Targets The potential targets of Diethyl Phthalate (DEP) were identified through searches in multiple databases, including ChEMBL ( https://www.ebi.ac.uk/chembl/ ), STITCH ( http://stitch.embl.de/ ), and SwissTargetPrediction ( http://www.swisstargetprediction.ch/ ). The data from these three databases were integrated to compile a comprehensive list of DEP's potential target genes. The protein interaction data for these targets were retrieved from the STRING database ( http://string-db.org/ ), which includes both known and predicted protein-protein interactions in humans. These interaction data were then imported into Cytoscape 3.7.2 to construct a protein-protein interaction network for DEP. The target genes identified through this network were subsequently uploaded to Metascape for functional enrichment analysis. This integrated approach enabled us to comprehensively identify the potential targets and associated pathways influenced by DEP exposure. 2.3. Target Construction of Diseases Disease-related target genes were identified by searching the GeneCards ( https://www.genecards.org/ ), OMIM ( https://www.omim.org/ ), and TTD databases. In GeneCards, genes were selected based on a "Gifts" score greater than 50, which was determined by reviewing relevant literature to ensure the genes were highly associated with the diseases of interest. The targets from these three databases were then merged, and duplicates were removed. This approach resulted in a comprehensive set of disease-related genes, which were further analyzed to understand their relevance to Diethyl Phthalate (DEP)-induced toxicity and psoriasis pathogenesis. The final disease-related gene library was constructed by integrating and deduplicating the data from all three sources. 2.4. Intersection of DEP Targets and Disease-Related Targets The intersection of DEP targets and disease-related genes was performed using the ggvenn package in R. This approach enabled the identification of common genes between the DEP target set and the disease-related gene list. 2.5. Identification of Hub Genes and Construction of Compound-Target-Disease Network The intersection genes of DEP targets and disease-related genes were initially uploaded to the STRING database ( https://string-db.org/ ) to construct a protein–protein interaction (PPI) network. Homo sapiens was selected as the species, with a minimum interaction score of 0.9. The generated PPI network was then imported into Cytoscape ( https://cytoscape.org/ ) for further visualization and analysis. Core genes were identified by ranking the nodes based on degree centrality, allowing the selection of the most significant targets involved in DEP-induced toxicity and disease mechanisms. Additionally, a compound-target-disease network was constructed in Cytoscape using the intersection genes. This network visualized the relationships between DEP, the intersected genes, and their associated diseases, providing a comprehensive overview of the connections between the compound, its potential targets, and relevant diseases. This approach further facilitated the identification of key targets in the context of DEP-related diseases. 2.6. GO and KEGG Pathway Analysis GO and KEGG pathway analyses were conducted to investigate the biological processes and pathways associated with the intersection of DEP targets and disease-related genes. Using the clusterProfiler package in R, GO enrichment was performed for biological processes (BP), cellular components (CC), and molecular functions (MF), along with KEGG pathway analysis. A p-value cutoff of 0.05 was applied to identify significantly enriched terms and pathways. Results were visualized using ggplot2, enrichplot, and circlize packages to generate bar plots, bubble plots, and circular pathway diagrams. 2.7. Molecular Docking Molecular docking was performed using DEP and the top 5 ranked targets identified from the PPI network. The 3D structure of DEP was obtained from the PubChem database ( https://pubchem.ncbi.nlm.nih.gov/ ), while the structures of the core target proteins were retrieved from the Protein Data Bank (PDB). For proteins not available in PDB, the UniProt database was consulted to gather additional information. The protein structures were prepared for docking using PyMOL 2.3.0, ensuring the removal of water molecules and any bound ligands. Docking simulations were carried out with AutoDock Vina 1.2.0, which provided the binding free energies and docking result files. The results were analyzed to evaluate the binding strength and interaction characteristics, with the most favorable docking poses selected for further investigation. Binding energies lower than 0 kcal·mol⁻¹ indicate that receptor-ligand binding is spontaneous without external energy, binding energies below − 5 kcal·mol⁻¹ reflect strong binding interactions, and values below − 7 kcal·mol⁻¹ suggest very strong binding. The docking results were visualized using PyMOL 2.3.0 to illustrate the interaction between DEP and the target proteins. 3. Results 3.1 Toxicological and Target Analysis of Diethyl Phthalate (DEP) Diethyl phthalate (DEP) was analyzed for its toxicological properties, molecular targets, and potential biological effects. The molecular structure of DEP (Fig. 1 A) was retrieved from PubChem and subjected to toxicity prediction using ADMETlab 2.0 and ProTox-II, which identified risks including neurotoxicity, hepatotoxicity, and blood-brain barrier (BBB) interactions (Fig. 1 B). To identify potential targets of DEP, we integrated data from ChEMBL, STITCH, and SwissTargetPrediction, yielding 287 unique target genes (Fig. 1 C). A protein-protein interaction (PPI) network was constructed using STRING and visualized in Cytoscape 3.7.2, revealing key target interactions (Fig. 1 D). Further analysis of transcription factor (TF) regulation identified RELA, NFKB1, and SP1 as the most significantly regulated TFs, along with EP300, TP53, and EGR1 (Fig. 1 E). These TFs are known to regulate immune signaling, inflammation, and cell survival, suggesting their involvement in DEP-induced toxicity. Gene Ontology (GO) enrichment analysis demonstrated that DEP-associated genes were significantly enriched in biological processes related to immune regulation, cellular responses to stimulus, and developmental pathways (Fig. 1 F). These findings highlight the potential impact of DEP on immune function, reproductive health, and cellular homeostasis, providing insights into its systemic toxicity and possible contributions to disease pathogenesis. 3.2 The impact of Diethyl Phthalate (DEP) on psoriasis The impact of Diethyl Phthalate (DEP) on psoriasis was assessed through gene intersection analysis, pathway enrichment, and molecular docking. A Venn diagram (Fig. 2 A) revealed 47 overlapping genes between DEP targets and psoriasis-associated genes, suggesting a mechanistic link between DEP exposure and psoriasis pathogenesis. Protein-protein interaction (PPI) network analysis (Fig. 2 B) identified SIRT1, HDAC1, BRD4, EP300, and EZH2 as key hub genes, indicating their central role in DEP-mediated effects. Functional enrichment analysis (Figs. 2 C, 2 D) demonstrated that DEP-associated genes were significantly involved in apoptotic signaling, histone modification, intracellular receptor signaling, and lysosomal function. KEGG pathway analysis (Figs. 2 E, 2 F) further highlighted DEP’s association with lysosome function, apoptosis, transcriptional misregulation in cancer, Polycomb repressive complex, ATP-dependent chromatin remodeling, and thyroid hormone signaling, indicating its broad influence on gene regulation and metabolic processes relevant to psoriasis development. A compound-target-disease network (Fig. 2 G) illustrated the interactions between DEP and psoriasis-related genes, reinforcing its potential contribution to disease progression. 3.3 Molecular Docking Analysis of DEP with Psoriasis-Associated Epigenetic Targets Molecular docking analysis (Fig. 3 ) confirmed strong binding affinities between DEP and core psoriasis-associated proteins, with binding energies ranging from − 5.9 to -7.5 kcal/mol. Notably, DEP exhibited the strongest interaction with SIRT1 (-7.5 kcal/mol), suggesting that DEP may interfere with SIRT1-mediated protective mechanisms against oxidative stress and inflammation. These findings suggest that DEP may exacerbate psoriasis by modulating apoptosis, epigenetic regulation, and immune responses, warranting further experimental validation. 4. Discussion In this study, we systematically investigated the molecular mechanisms through which diethyl phthalate (DEP) may contribute to the pathogenesis of psoriasis. By integrating network toxicology, protein-protein interaction (PPI) network analysis, functional enrichment analysis (GO and KEGG), and molecular docking, we identified key DEP-targeted genes and their potential roles in disease-related pathways. Our findings indicate that DEP exposure may influence immune signaling, epigenetic modifications, and apoptosis, shedding light on its potential dermatotoxic effects and broader implications for public health. Our toxicological analysis revealed that DEP poses significant systemic toxicity risks, including neurotoxicity, hepatotoxicity, and blood-brain barrier (BBB) disruption. The ability of DEP to cross the BBB suggests its potential neurotoxic effects, which have been linked to alterations in cell proliferation, survival, and apoptosis[ 17 ]. Additionally, DEP-induced hepatotoxicity has been associated with oxidative stress, genotoxicity, and modulation of molecular pathways[ 18 ]. Beyond these systemic effects, our enrichment analysis demonstrated that DEP-associated genes are involved in fundamental biological processes and are regulated by critical transcription factors (TFs), particularly RELA, NFKB1, and SP1. As essential components of the NF-κB signaling pathway, RELA and NFKB1 play pivotal roles in inflammation, immune regulation, and cell survival[ 19 ]. Aberrant activation of NF-κB has been implicated in the pathogenesis of chronic inflammatory skin diseases, including psoriasis[ 20 ]. DEP exposure may enhance NF-κB signaling, thereby amplifying inflammatory responses in the skin. Additionally, Sp1 was involved in diverse cellular functions, including oxidative stress and inflammation [ 20 , 21 ]. GO enrichment analysis further underscored DEP’s involvement in immune regulation, response to stimulus, and homeostasis—biological processes central to inflammatory skin disorders (Fig. 2 ). These findings highlight DEP as a potential environmental trigger for inflammatory skin diseases, warranting further investigation into its pathogenic mechanisms. As an environmental pollutant, DEP is widely detected in air, water, soil, and human biological fluids, raising concerns regarding long-term low-dose exposure and its cumulative health effects [ 22 ]. Notably, DEP exposure is not limited to occupational settings but extends to daily-use consumer products, including cosmetics, personal care products, and pharmaceuticals, leading to chronic and repeated skin contact [ 23 ]. The dermal route represents a significant, yet often underappreciated, pathway of DEP absorption. Given that individuals with psoriasis have compromised skin barriers and increased permeability, DEP absorption may be enhanced[ 24 ]. These findings underscore the urgent need for regulatory measures to limit DEP exposure, particularly for vulnerable populations, and highlight the necessity for further research on DEP penetration dynamics in compromised skin. Our findings suggest that DEP may contribute to psoriasis pathogenesis through multiple mechanisms, including the dysregulation of apoptotic signaling, epigenetic modifications, and lysosomal dysfunction. GO and KEGG enrichment analyses revealed significant enrichment of DEP-associated genes in apoptotic signaling pathways, highlighting its potential role in keratinocyte hyperproliferation and sustained inflammation in psoriasis. Keratinocytes play a central role in initiating and sustaining psoriasis-associated inflammation, and DEP may promote keratinocyte hyperproliferation and prolonged inflammation by interfering with apoptotic pathways, thereby exacerbating psoriatic lesions [ 25 ]. Additionally, histone modification-related pathways, including histone deacetylases (HDACs) and chromatin remodeling complexes, were significantly enriched. Given that environmental risk factors can influence psoriasis by altering DNA methylation, histone modifications, and non-coding RNA expression, DEP exposure may modify epigenetic regulation of inflammatory and immune-related genes, contributing to disease persistence[ 26 ]. F Furthermore, DEP exposure was linked to lysosomal dysfunction, implicating defects in autophagy and antigen processing. Lysosomal degradation mechanisms play a crucial role in psoriasis pathophysiology, as impaired autophagy can lead to sustained inflammation and uncontrolled keratinocyte proliferation and differentiation[ 27 , 28 ]. These findings underscore DEP’s potential role in modulating key molecular pathways in psoriasis and emphasize the need for further experimental studies. Molecular docking analysis revealed that DEP exhibited strong binding affinities to key proteins implicated in psoriasis, including SIRT1, HDAC1, BRD4, EP300, and EZH2. Among them, DEP showed a particularly strong interaction with SIRT1 (-7.5 kcal/mol), suggesting potential interference with its regulatory function. Notably, SIRT1 is downregulated in psoriatic lesions, and its activation has been shown to mitigate oxidative stress and inflammation by inhibiting the MAPK, NF-κB, and STAT3 pathways[ 29 ]. Thus, DEP’s binding to SIRT1 may disrupt these protective mechanisms, exacerbating oxidative damage and inflammatory responses in psoriasis. In addition to SIRT1, HDAC1, as histone deacetylases (HDACs), regulate chromatin structure and gene transcription. Their aberrant histone modifications may contribute to psoriasis pathogenesis by altering keratinocyte proliferation, differentiation, and inflammatory responses[ 30 ].According to previous studies, BRD4 is upregulated in psoriatic skin tissues, and its silencing has been shown to suppress keratinocyte migration, proliferation, and inflammation[ 31 ]. The strong binding affinity between DEP and BRD4 suggests that DEP exposure may interfere with chromatin accessibility and inflammatory gene transcription, thereby exacerbating psoriasis symptoms. Furthermore, the strong binding affinity between DEP and EZH2 is particularly noteworthy. Studies have demonstrated that the CDK4/6-EZH2 pathway is hyperactivated in both human and mouse psoriatic lesions, potentially triggering a methylation-induced activation of STAT3, leading to the onset and progression of psoriasis[ 32 ].These results indicate that DEP may aggravate psoriasis by modulating key epigenetic regulators and inflammatory pathways, providing novel insights into the environmental contribution to psoriasis pathogenesis. This study is based on bioinformatics predictions and computational modeling, lacking direct experimental validation in vitro or in vivo. While our findings provide valuable insights into potential molecular mechanisms, the absence of experimental confirmation limits the direct applicability of these results. Additionally, individual variations, such as genetic predisposition, skin barrier integrity, and microbiome composition, were not accounted for in our analysis, which may significantly influence DEP absorption and its downstream effects in different populations. Moreover, this study did not examine DEP’s primary metabolite, monoethyl phthalate (MEP), which may exhibit distinct biological effects and contribute differently to disease pathogenesis. Future research should focus on integrating in vitro and in vivo experiments to validate these findings, assessing personalized exposure risks, and investigating the metabolic fate of DEP and its derivatives to obtain a more comprehensive understanding of its impact on psoriasis. 5. Conclusion This study provides novel insights into the potential role of DEP in the pathogenesis of psoriasis, highlighting its influence on inflammatory gene expression through epigenetic regulation. Our findings suggest that DEP may exert its effects via key epigenetic modulators, including SIRT1, EP300, HDAC1, BRD4, and EZH2, offering a new hypothesis linking environmental pollutants to psoriasis. By establishing DEP as a potential aggravating factor in psoriasis, this study contributes to the growing evidence of environmental pollutants as modulators of skin disease progression. These findings underscore the need for further research to validate the mechanisms identified and explore potential intervention strategies. In the future, this work may guide the development of preventive measures and personalized therapeutic approaches for DEP-related skin disorders, supporting advancements in precision medicine. Declarations Funding This study was supported by the Sichuan Medical Youth Innovation Research Project (Grant No. Q23014) and the Suining Health Science and Technology Project (Grant No. 24CJDFB07). CRediT authorship contribution statement Linli Liu: Conceptualization, Methodology, Formal analysis, Data curation, Writing – original draft, Writing – review & editing, Supervision, Funding acquisition. Lingli Deng: Methodology, Formal analysis, Data curation, Writing – original draft. Chuan Ye: Methodology, Investigation, Formal analysis, Writing – original draft. Tingting Liu: Investigation, Visualization. Chunshui Yu: Conceptualization, Supervision, Validation, Writing – review & editing. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data Availability Data will be made available on request. Acknowledgements The authors gratefully acknowledge the support provided by the platform of Suining Central Hospital. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6750557","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":472747575,"identity":"01090a79-3eb7-4e80-b239-79b688802c42","order_by":0,"name":"Linli Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAx0lEQVRIiWNgGAWjYBACefnnBw584PnHw8beQKQWw4acxIczZA7I8fEcINaaAwnGxjw2B4zlJBKI1MHYcCBNckbOncQ2yccbbzDU2EQT1MLO2HhM4sOZZ4lt0mnFFgzH0nIbCNrSzJAmObOHGaglx0yCseEwYS0MxxjMpHn/AbVIniFWyxkGoPd5DhuzSfAQqcVwBg8wkHnS5Nh4gH5JIMYv8hLsoKi04ZFvP7zxxocaGyIchgQMiI4aJC2k6hgFo2AUjIKRAQC2nT904cyMcQAAAABJRU5ErkJggg==","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":true,"prefix":"","firstName":"Linli","middleName":"","lastName":"Liu","suffix":""},{"id":472747576,"identity":"76f1d590-ae04-42c5-bb99-74c9b008a364","order_by":1,"name":"Chuan Ye","email":"","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chuan","middleName":"","lastName":"Ye","suffix":""},{"id":472747577,"identity":"722cfba7-7620-4037-8b19-bb23b7e9553d","order_by":2,"name":"Lingli Deng","email":"","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lingli","middleName":"","lastName":"Deng","suffix":""},{"id":472747578,"identity":"c6f237d8-c4cf-4431-882d-568b4fbfc74e","order_by":3,"name":"Tingting Liu","email":"","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Liu","suffix":""},{"id":472747579,"identity":"3a1696d8-c007-4b69-9e01-7190362ab31a","order_by":4,"name":"Chunshui Yu","email":"","orcid":"","institution":"Suining Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chunshui","middleName":"","lastName":"Yu","suffix":""}],"badges":[],"createdAt":"2025-05-26 11:53:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6750557/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6750557/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84905517,"identity":"6e7ed7ac-67b6-49c6-b979-89acc613a366","added_by":"auto","created_at":"2025-06-18 15:49:26","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1398384,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eToxicological and potential target analysis of Diethyl phthalate (DEP). \u003c/strong\u003e(A) The molecular structure of DEP. (B) Radar chart illustrating the predicted toxicological properties of DEP, including hepatotoxicity, neurotoxicity, nephrotoxicity, and interactions with CYP enzymes. (C) Venn diagram showing the intersection of predicted DEP targets from ChEMBL, STITCH, and SwissTargetPrediction databases. (D) Network visualization of DEP-regulated genes and their associated biological processes. (E) Key transcription factors (TFs) predicted to be regulated by DEP, ranked by statistical significance (-log10(P)). (F) Gene Ontology (GO) enrichment analysis of DEP-associated genes, highlighting biological processes affected by DEP exposure, including regulation of biological processes, response to stimulus, and cellular process.\u003c/p\u003e","description":"","filename":"Figure1..jpg","url":"https://assets-eu.researchsquare.com/files/rs-6750557/v1/acf33707024c1ce7719ee970.jpg"},{"id":84905066,"identity":"a27de95d-21e4-4095-836e-6b6811f2e440","added_by":"auto","created_at":"2025-06-18 15:41:26","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1880253,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunctional enrichment analysis of differentially expressed genes (DEGs) between Diethyl phthalate (DEP) exposure and psoriasis. \u003c/strong\u003e(A) Venn diagram showing the overlap of DEGs between DEP-associated targets (red) and psoriasis-related genes (blue), identifying 47 shared genes. (B) Protein-protein interaction (PPI) network of the shared genes, highlighting hub genes involved in epigenetic regulation, inflammatory signaling, and immune modulation. (C) Gene Ontology (GO) enrichment analysis of DEP-psoriasis DEGs, categorized into biological process (BP), cellular component (CC), and molecular function (MF), with color intensity representing adjusted p-values. (D) Bar plot summarizing GO enrichment results across different ontology categories. (E, F) KEGG pathway enrichment analysis, displaying significantly enriched pathways such as lysosome function, apoptosis, lysine degradation, transcriptional misregulation in cancer, and chromatin remodeling, with node sizes indicating gene ratio and color intensity reflecting statistical significance. (G) Regulatory network illustrating the interactions between DEP, key hub genes, and psoriasis.\u003c/p\u003e","description":"","filename":"Figure2..jpg","url":"https://assets-eu.researchsquare.com/files/rs-6750557/v1/f82af8a46eef6def0ce98260.jpg"},{"id":84904196,"identity":"5321e8d1-f68f-43f1-be8b-8d859e21e08b","added_by":"auto","created_at":"2025-06-18 15:33:26","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3138511,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMolecular docking results of Diethyl Phthalate (DEP) with core genes involved in psoriasis. \u003c/strong\u003eThe figure illustrates the molecular docking interactions between DEP and key target proteins associated with psoriasis. For each protein, the 3D structure (left) is shown along with the detailed docking interaction (right), highlighting the binding pocket and key interacting residues. The binding energy (kcal/mol) for each interaction is provided.\u003c/p\u003e","description":"","filename":"Figure3..jpg","url":"https://assets-eu.researchsquare.com/files/rs-6750557/v1/02182dc1b1dc4bc9d4fe30e6.jpg"},{"id":100373049,"identity":"85b8f49c-807e-42f7-9a10-05175c4deb74","added_by":"auto","created_at":"2026-01-16 08:13:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7164807,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6750557/v1/e1ac545c-ea82-44b3-9775-672a47bba9ed.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Network Toxicology and Molecular Docking Reveal Diethyl Phthalate as a Potential Epigenetic Modulator in Psoriasis Pathogenesis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eDiethyl phthalate (DEP), a widely used phthalate ester, is commonly found in industrial and consumer products, including plastics, cosmetics, personal care products, and pharmaceuticals[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Due to its extensive use and environmental persistence, DEP has been detected in air, water, soil, and human biological samples, indicating widespread human exposure through ingestion, inhalation, and dermal absorption[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Notably, dermal exposure constitutes a significant yet often overlooked route of DEP absorption, particularly for individuals frequently using personal care products such as perfumes, lotions, and sunscreens, where DEP serves as a solvent and penetration enhancer[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Given its lipophilic properties, DEP can readily penetrate the stratum corneum, facilitating systemic absorption and increasing the risk of bioaccumulation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe skin acts as a primary barrier against environmental toxins, but in individuals with psoriasis and compromised skin barrier function, increased permeability to environmental pollutants has been observed[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These conditions are characterized by defects in filaggrin, tight junctions, and lipid composition, which disrupt epidermal integrity and facilitate the transdermal absorption of harmful chemicals, including DEP [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. DEP accumulation in the skin and systemic circulation raises concerns regarding its potential impact on immune homeostasis and inflammatory responses [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Despite these concerns, the specific molecular mechanisms by which DEP contributes to psoriasis remain unclear, necessitating further investigation.\u003c/p\u003e \u003cp\u003ePsoriasis are chronic inflammatory skin diseases influenced by genetic predisposition, immune dysregulation, and environmental factors[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Although genome-wide association studies (GWAS) have identified multiple susceptibility loci, growing evidence suggests that environmental pollutants can serve as disease triggers through epigenetic modifications [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Epigenetic alterations, including DNA methylation, histone modifications, and non-coding RNA regulation, modulate gene expression without altering the genetic sequence [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In psoriasis, histone modifications are associated with sustained inflammatory responses and keratinocyte hyperproliferation[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Importantly, reversing these epigenetic modifications has been shown to mitigate disease severity, highlighting epigenetic pathways as potential therapeutic targets [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Given that DEP has been implicated in disrupting endocrine and immune signaling pathways [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], it is plausible that DEP exposure contributes to psoriasis through epigenetic and transcriptional dysregulation. However, a systematic investigation into these molecular mechanisms remains lacking.\u003c/p\u003e \u003cp\u003ePrevious studies on DEP toxicity have primarily focused on its reproductive and metabolic effects, while its impact on dermatological conditions remains poorly understood [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Although some evidence suggests that DEP may modulate immune responses and inflammatory signaling, its direct role in inflammatory skin diseases such as psoriasis remains uncharacterized [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. DEP may contribute to their exacerbation via epigenetic modifications, chromatin remodeling, and transcriptional regulation.\u003c/p\u003e \u003cp\u003eTo bridge this knowledge gap, the present study systematically investigates the molecular mechanisms through which DEP may contribute to psoriasis pathogenesis. By integrating network toxicology, protein-protein interaction (PPI) analysis, functional enrichment analysis (GO and KEGG), and molecular docking, we explore potential interactions between DEP and key genes associated with psoriasis. This study provides the first comprehensive investigation into the molecular mechanisms linking DEP exposure to psoriasis, offering novel insights into the dermatotoxic potential of DEP as an environmental pollutant. A deeper understanding of these interactions may contribute to the development of targeted therapeutic strategies and enhance efforts to mitigate the impact of environmental pollutants on skin health.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Network Toxicological Analysis of DEP\u003c/h2\u003e \u003cp\u003eThe standard SMILES format for the active ingredient Diethyl Phthalate (DEP) was obtained from the PubChem platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubchem.ncbi.nlm.nih.gov/\u003c/span\u003e\u003cspan address=\"https://pubchem.ncbi.nlm.nih.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). This sequence was then imported into ADMETlab 2.0 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://admetmesh.scbdd.com/\u003c/span\u003e\u003cspan address=\"https://admetmesh.scbdd.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and ProTox-II (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://comptox.charite.de/protox3/\u003c/span\u003e\u003cspan address=\"https://comptox.charite.de/protox3/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) software tools for comprehensive toxicity analysis. These platforms provided predictions regarding the toxicological properties of DEP, including potential effects on various biological systems.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Collection of DEP Targets\u003c/h2\u003e \u003cp\u003eThe potential targets of Diethyl Phthalate (DEP) were identified through searches in multiple databases, including ChEMBL (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ebi.ac.uk/chembl/\u003c/span\u003e\u003cspan address=\"https://www.ebi.ac.uk/chembl/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), STITCH (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://stitch.embl.de/\u003c/span\u003e\u003cspan address=\"http://stitch.embl.de/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and SwissTargetPrediction (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.swisstargetprediction.ch/\u003c/span\u003e\u003cspan address=\"http://www.swisstargetprediction.ch/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The data from these three databases were integrated to compile a comprehensive list of DEP's potential target genes. The protein interaction data for these targets were retrieved from the STRING database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://string-db.org/\u003c/span\u003e\u003cspan address=\"http://string-db.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), which includes both known and predicted protein-protein interactions in humans. These interaction data were then imported into Cytoscape 3.7.2 to construct a protein-protein interaction network for DEP. The target genes identified through this network were subsequently uploaded to Metascape for functional enrichment analysis. This integrated approach enabled us to comprehensively identify the potential targets and associated pathways influenced by DEP exposure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Target Construction of Diseases\u003c/h2\u003e \u003cp\u003eDisease-related target genes were identified by searching the GeneCards (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.genecards.org/\u003c/span\u003e\u003cspan address=\"https://www.genecards.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), OMIM (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.omim.org/\u003c/span\u003e\u003cspan address=\"https://www.omim.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and TTD databases. In GeneCards, genes were selected based on a \"Gifts\" score greater than 50, which was determined by reviewing relevant literature to ensure the genes were highly associated with the diseases of interest. The targets from these three databases were then merged, and duplicates were removed. This approach resulted in a comprehensive set of disease-related genes, which were further analyzed to understand their relevance to Diethyl Phthalate (DEP)-induced toxicity and psoriasis pathogenesis. The final disease-related gene library was constructed by integrating and deduplicating the data from all three sources.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Intersection of DEP Targets and Disease-Related Targets\u003c/h2\u003e \u003cp\u003eThe intersection of DEP targets and disease-related genes was performed using the ggvenn package in R. This approach enabled the identification of common genes between the DEP target set and the disease-related gene list.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Identification of Hub Genes and Construction of Compound-Target-Disease Network\u003c/h2\u003e \u003cp\u003eThe intersection genes of DEP targets and disease-related genes were initially uploaded to the STRING database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://string-db.org/\u003c/span\u003e\u003cspan address=\"https://string-db.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to construct a protein\u0026ndash;protein interaction (PPI) network. Homo sapiens was selected as the species, with a minimum interaction score of 0.9. The generated PPI network was then imported into Cytoscape (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cytoscape.org/\u003c/span\u003e\u003cspan address=\"https://cytoscape.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) for further visualization and analysis. Core genes were identified by ranking the nodes based on degree centrality, allowing the selection of the most significant targets involved in DEP-induced toxicity and disease mechanisms.\u003c/p\u003e \u003cp\u003eAdditionally, a compound-target-disease network was constructed in Cytoscape using the intersection genes. This network visualized the relationships between DEP, the intersected genes, and their associated diseases, providing a comprehensive overview of the connections between the compound, its potential targets, and relevant diseases. This approach further facilitated the identification of key targets in the context of DEP-related diseases.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6. GO and KEGG Pathway Analysis\u003c/h2\u003e \u003cp\u003eGO and KEGG pathway analyses were conducted to investigate the biological processes and pathways associated with the intersection of DEP targets and disease-related genes. Using the clusterProfiler package in R, GO enrichment was performed for biological processes (BP), cellular components (CC), and molecular functions (MF), along with KEGG pathway analysis. A p-value cutoff of 0.05 was applied to identify significantly enriched terms and pathways. Results were visualized using ggplot2, enrichplot, and circlize packages to generate bar plots, bubble plots, and circular pathway diagrams.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7. Molecular Docking\u003c/h2\u003e \u003cp\u003eMolecular docking was performed using DEP and the top 5 ranked targets identified from the PPI network. The 3D structure of DEP was obtained from the PubChem database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubchem.ncbi.nlm.nih.gov/\u003c/span\u003e\u003cspan address=\"https://pubchem.ncbi.nlm.nih.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), while the structures of the core target proteins were retrieved from the Protein Data Bank (PDB). For proteins not available in PDB, the UniProt database was consulted to gather additional information. The protein structures were prepared for docking using PyMOL 2.3.0, ensuring the removal of water molecules and any bound ligands. Docking simulations were carried out with AutoDock Vina 1.2.0, which provided the binding free energies and docking result files.\u003c/p\u003e \u003cp\u003eThe results were analyzed to evaluate the binding strength and interaction characteristics, with the most favorable docking poses selected for further investigation. Binding energies lower than 0 kcal\u0026middot;mol⁻\u0026sup1; indicate that receptor-ligand binding is spontaneous without external energy, binding energies below \u0026minus;\u0026thinsp;5 kcal\u0026middot;mol⁻\u0026sup1; reflect strong binding interactions, and values below \u0026minus;\u0026thinsp;7 kcal\u0026middot;mol⁻\u0026sup1; suggest very strong binding. The docking results were visualized using PyMOL 2.3.0 to illustrate the interaction between DEP and the target proteins.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Toxicological and Target Analysis of Diethyl Phthalate (DEP)\u003c/h2\u003e \u003cp\u003eDiethyl phthalate (DEP) was analyzed for its toxicological properties, molecular targets, and potential biological effects. The molecular structure of DEP (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA) was retrieved from PubChem and subjected to toxicity prediction using ADMETlab 2.0 and ProTox-II, which identified risks including neurotoxicity, hepatotoxicity, and blood-brain barrier (BBB) interactions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). To identify potential targets of DEP, we integrated data from ChEMBL, STITCH, and SwissTargetPrediction, yielding 287 unique target genes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). A protein-protein interaction (PPI) network was constructed using STRING and visualized in Cytoscape 3.7.2, revealing key target interactions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). Further analysis of transcription factor (TF) regulation identified RELA, NFKB1, and SP1 as the most significantly regulated TFs, along with EP300, TP53, and EGR1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE). These TFs are known to regulate immune signaling, inflammation, and cell survival, suggesting their involvement in DEP-induced toxicity. Gene Ontology (GO) enrichment analysis demonstrated that DEP-associated genes were significantly enriched in biological processes related to immune regulation, cellular responses to stimulus, and developmental pathways (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). These findings highlight the potential impact of DEP on immune function, reproductive health, and cellular homeostasis, providing insights into its systemic toxicity and possible contributions to disease pathogenesis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.2 The impact of Diethyl Phthalate (DEP) on psoriasis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe impact of Diethyl Phthalate (DEP) on psoriasis was assessed through gene intersection analysis, pathway enrichment, and molecular docking. A Venn diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) revealed 47 overlapping genes between DEP targets and psoriasis-associated genes, suggesting a mechanistic link between DEP exposure and psoriasis pathogenesis. Protein-protein interaction (PPI) network analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB) identified SIRT1, HDAC1, BRD4, EP300, and EZH2 as key hub genes, indicating their central role in DEP-mediated effects. Functional enrichment analysis (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD) demonstrated that DEP-associated genes were significantly involved in apoptotic signaling, histone modification, intracellular receptor signaling, and lysosomal function. KEGG pathway analysis (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF) further highlighted DEP\u0026rsquo;s association with lysosome function, apoptosis, transcriptional misregulation in cancer, Polycomb repressive complex, ATP-dependent chromatin remodeling, and thyroid hormone signaling, indicating its broad influence on gene regulation and metabolic processes relevant to psoriasis development. A compound-target-disease network (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG) illustrated the interactions between DEP and psoriasis-related genes, reinforcing its potential contribution to disease progression.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Molecular Docking Analysis of DEP with Psoriasis-Associated Epigenetic Targets\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eMolecular docking analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) confirmed strong binding affinities between DEP and core psoriasis-associated proteins, with binding energies ranging from \u0026minus;\u0026thinsp;5.9 to -7.5 kcal/mol. Notably, DEP exhibited the strongest interaction with SIRT1 (-7.5 kcal/mol), suggesting that DEP may interfere with SIRT1-mediated protective mechanisms against oxidative stress and inflammation. These findings suggest that DEP may exacerbate psoriasis by modulating apoptosis, epigenetic regulation, and immune responses, warranting further experimental validation.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, we systematically investigated the molecular mechanisms through which diethyl phthalate (DEP) may contribute to the pathogenesis of psoriasis. By integrating network toxicology, protein-protein interaction (PPI) network analysis, functional enrichment analysis (GO and KEGG), and molecular docking, we identified key DEP-targeted genes and their potential roles in disease-related pathways. Our findings indicate that DEP exposure may influence immune signaling, epigenetic modifications, and apoptosis, shedding light on its potential dermatotoxic effects and broader implications for public health.\u003c/p\u003e \u003cp\u003eOur toxicological analysis revealed that DEP poses significant systemic toxicity risks, including neurotoxicity, hepatotoxicity, and blood-brain barrier (BBB) disruption. The ability of DEP to cross the BBB suggests its potential neurotoxic effects, which have been linked to alterations in cell proliferation, survival, and apoptosis[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Additionally, DEP-induced hepatotoxicity has been associated with oxidative stress, genotoxicity, and modulation of molecular pathways[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Beyond these systemic effects, our enrichment analysis demonstrated that DEP-associated genes are involved in fundamental biological processes and are regulated by critical transcription factors (TFs), particularly RELA, NFKB1, and SP1. As essential components of the NF-κB signaling pathway, RELA and NFKB1 play pivotal roles in inflammation, immune regulation, and cell survival[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Aberrant activation of NF-κB has been implicated in the pathogenesis of chronic inflammatory skin diseases, including psoriasis[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. DEP exposure may enhance NF-κB signaling, thereby amplifying inflammatory responses in the skin. Additionally, Sp1 was involved in diverse cellular functions, including oxidative stress and inflammation [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. GO enrichment analysis further underscored DEP\u0026rsquo;s involvement in immune regulation, response to stimulus, and homeostasis\u0026mdash;biological processes central to inflammatory skin disorders (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These findings highlight DEP as a potential environmental trigger for inflammatory skin diseases, warranting further investigation into its pathogenic mechanisms.\u003c/p\u003e \u003cp\u003eAs an environmental pollutant, DEP is widely detected in air, water, soil, and human biological fluids, raising concerns regarding long-term low-dose exposure and its cumulative health effects [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Notably, DEP exposure is not limited to occupational settings but extends to daily-use consumer products, including cosmetics, personal care products, and pharmaceuticals, leading to chronic and repeated skin contact [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The dermal route represents a significant, yet often underappreciated, pathway of DEP absorption. Given that individuals with psoriasis have compromised skin barriers and increased permeability, DEP absorption may be enhanced[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. These findings underscore the urgent need for regulatory measures to limit DEP exposure, particularly for vulnerable populations, and highlight the necessity for further research on DEP penetration dynamics in compromised skin.\u003c/p\u003e \u003cp\u003eOur findings suggest that DEP may contribute to psoriasis pathogenesis through multiple mechanisms, including the dysregulation of apoptotic signaling, epigenetic modifications, and lysosomal dysfunction. GO and KEGG enrichment analyses revealed significant enrichment of DEP-associated genes in apoptotic signaling pathways, highlighting its potential role in keratinocyte hyperproliferation and sustained inflammation in psoriasis. Keratinocytes play a central role in initiating and sustaining psoriasis-associated inflammation, and DEP may promote keratinocyte hyperproliferation and prolonged inflammation by interfering with apoptotic pathways, thereby exacerbating psoriatic lesions [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Additionally, histone modification-related pathways, including histone deacetylases (HDACs) and chromatin remodeling complexes, were significantly enriched. Given that environmental risk factors can influence psoriasis by altering DNA methylation, histone modifications, and non-coding RNA expression, DEP exposure may modify epigenetic regulation of inflammatory and immune-related genes, contributing to disease persistence[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. F Furthermore, DEP exposure was linked to lysosomal dysfunction, implicating defects in autophagy and antigen processing. Lysosomal degradation mechanisms play a crucial role in psoriasis pathophysiology, as impaired autophagy can lead to sustained inflammation and uncontrolled keratinocyte proliferation and differentiation[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. These findings underscore DEP\u0026rsquo;s potential role in modulating key molecular pathways in psoriasis and emphasize the need for further experimental studies.\u003c/p\u003e \u003cp\u003eMolecular docking analysis revealed that DEP exhibited strong binding affinities to key proteins implicated in psoriasis, including SIRT1, HDAC1, BRD4, EP300, and EZH2. Among them, DEP showed a particularly strong interaction with SIRT1 (-7.5 kcal/mol), suggesting potential interference with its regulatory function. Notably, SIRT1 is downregulated in psoriatic lesions, and its activation has been shown to mitigate oxidative stress and inflammation by inhibiting the MAPK, NF-κB, and STAT3 pathways[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Thus, DEP\u0026rsquo;s binding to SIRT1 may disrupt these protective mechanisms, exacerbating oxidative damage and inflammatory responses in psoriasis. In addition to SIRT1, HDAC1, as histone deacetylases (HDACs), regulate chromatin structure and gene transcription. Their aberrant histone modifications may contribute to psoriasis pathogenesis by altering keratinocyte proliferation, differentiation, and inflammatory responses[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].According to previous studies, BRD4 is upregulated in psoriatic skin tissues, and its silencing has been shown to suppress keratinocyte migration, proliferation, and inflammation[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The strong binding affinity between DEP and BRD4 suggests that DEP exposure may interfere with chromatin accessibility and inflammatory gene transcription, thereby exacerbating psoriasis symptoms. Furthermore, the strong binding affinity between DEP and EZH2 is particularly noteworthy. Studies have demonstrated that the CDK4/6-EZH2 pathway is hyperactivated in both human and mouse psoriatic lesions, potentially triggering a methylation-induced activation of STAT3, leading to the onset and progression of psoriasis[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].These results indicate that DEP may aggravate psoriasis by modulating key epigenetic regulators and inflammatory pathways, providing novel insights into the environmental contribution to psoriasis pathogenesis.\u003c/p\u003e \u003cp\u003eThis study is based on bioinformatics predictions and computational modeling, lacking direct experimental validation in vitro or in vivo. While our findings provide valuable insights into potential molecular mechanisms, the absence of experimental confirmation limits the direct applicability of these results. Additionally, individual variations, such as genetic predisposition, skin barrier integrity, and microbiome composition, were not accounted for in our analysis, which may significantly influence DEP absorption and its downstream effects in different populations. Moreover, this study did not examine DEP\u0026rsquo;s primary metabolite, monoethyl phthalate (MEP), which may exhibit distinct biological effects and contribute differently to disease pathogenesis. Future research should focus on integrating in vitro and in vivo experiments to validate these findings, assessing personalized exposure risks, and investigating the metabolic fate of DEP and its derivatives to obtain a more comprehensive understanding of its impact on psoriasis.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study provides novel insights into the potential role of DEP in the pathogenesis of psoriasis, highlighting its influence on inflammatory gene expression through epigenetic regulation. Our findings suggest that DEP may exert its effects via key epigenetic modulators, including SIRT1, EP300, HDAC1, BRD4, and EZH2, offering a new hypothesis linking environmental pollutants to psoriasis. By establishing DEP as a potential aggravating factor in psoriasis, this study contributes to the growing evidence of environmental pollutants as modulators of skin disease progression. These findings underscore the need for further research to validate the mechanisms identified and explore potential intervention strategies. In the future, this work may guide the development of preventive measures and personalized therapeutic approaches for DEP-related skin disorders, supporting advancements in precision medicine.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;This study was supported by the Sichuan Medical Youth Innovation Research Project (Grant No. Q23014) and the Suining Health Science and Technology Project (Grant No. 24CJDFB07).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u003c/strong\u003e\u003cbr\u003e\u003cstrong\u003eLinli Liu:\u003c/strong\u003e Conceptualization, Methodology, Formal analysis, Data curation, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing, Supervision, Funding acquisition.\u003cbr\u003e\u003cstrong\u003eLingli Deng:\u003c/strong\u003e Methodology, Formal analysis, Data curation, Writing \u0026ndash; original draft.\u003cbr\u003e\u003cstrong\u003eChuan Ye:\u003c/strong\u003e Methodology, Investigation, Formal analysis, Writing \u0026ndash; original draft.\u003cbr\u003e\u003cstrong\u003eTingting Liu:\u003c/strong\u003e Investigation, Visualization.\u003cbr\u003e\u003cstrong\u003eChunshui Yu:\u003c/strong\u003e Conceptualization, Supervision, Validation, Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Data will be made available on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors gratefully acknowledge the support provided by the platform of Suining Central Hospital.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVerma CR, Khare T, Chakraborty P, Gosavi SM, Petrt\u0026yacute;l M, Kalous L et al (2024) Impact of diethyl phthalate on freshwater planarian behaviour, regeneration, and antioxidant defence. 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J Clin Invest 130(11):5765\u0026ndash;5781. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1172/JCI134217\u003c/span\u003e\u003cspan address=\"10.1172/JCI134217\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Diethyl phthalate (DEP), Psoriasis, Network toxicology, Molecular docking, Epigenetic regulation","lastPublishedDoi":"10.21203/rs.3.rs-6750557/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6750557/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDiethyl phthalate (DEP), a widely used phthalate ester, is extensively detected in environmental and human biological samples, indicating significant exposure through ingestion, inhalation, and dermal absorption. Psoriasis, a chronic inflammatory skin disease, is characterized by immune dysregulation and epigenetic alterations. However, the potential contribution of DEP to psoriasis pathogenesis remains poorly understood. This study employed a network toxicology approach, integrating protein-protein interaction (PPI) network analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and molecular docking to systematically evaluate the potential role of DEP in psoriasis. A total of 47 intersecting genes were identified between DEP targets and psoriasis-related genes. Key hub genes, including SIRT1, HDAC1, BRD4, EP300, and EZH2, were identified, highlighting their possible involvement in DEP-mediated toxicity. Enrichment analysis revealed significant associations with apoptosis, chromatin remodeling, and immune regulation. Molecular docking results demonstrated strong binding affinities between DEP and core proteins, particularly SIRT1. These findings suggest that DEP may exacerbate psoriasis through epigenetic modulation and immune dysregulation. This study provides a novel mechanistic link between environmental exposure and inflammatory skin disease and underscores the need for further experimental validation.\u003c/p\u003e","manuscriptTitle":"Network Toxicology and Molecular Docking Reveal Diethyl Phthalate as a Potential Epigenetic Modulator in Psoriasis Pathogenesis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 15:33:22","doi":"10.21203/rs.3.rs-6750557/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"645ec8c7-46dd-4d97-8376-57105036f5b8","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-15T17:23:48+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-18 15:33:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6750557","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6750557","identity":"rs-6750557","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}