{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T05:04:42Z","timestamp":1780031082521,"version":"3.53.1"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Psoriasis is a chronic immune-mediated inflammatory skin disease driven by dysregulation of the IL-23\/IL-17 axis and influenced by genetic and environmental factors. The role and molecular mechanisms of the environmental pollutant dibenzo-p-dioxins, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in psoriasis remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      An integrative strategy combining network toxicology, machine learning, bioinformatics analysis, molecular simulation, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      keratinocyte qRT\u2013PCR validation was employed to systematically investigate the potential toxicity and molecular mechanisms of TCDD in psoriasis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eighty-seven overlapping genes were identified between TCDD-related targets and psoriasis-associated genes and were mainly enriched in IL- 17-, chemokine-, MAPK\/ ERK-, and GPCR-related signaling pathways. Machine learning identified five core target genes\u2014LCK, MMP9, CXCR2, PTAFR, and CCNB1\u2014which were significantly upregulated in psoriatic lesions, showed strong diagnostic performance within the analyzed datasets, and were associated with local immune infiltration patterns. Structural analyses supported potential interactions between TCDD and these core targets, with CXCR2 showing the most favorable predicted docking score. A 24-h keratinocyte TCDD-response signature showed significant concordance with psoriatic lesional transcriptomes, and keratinocyte qRT\u2013PCR validation showed increased expression of LCK, MMP9, CXCR2, and PTAFR, whereas CCNB1 showed only a modest change. In biologic-therapy cohorts, core genes were downregulated after 12 weeks, and higher baseline MMP9 was associated with poorer clinical improvement and may have potential relevance to treatment response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our integrative analyses identify TCDD-associated genes and pathways potentially involved in psoriasis immune dysregulation. Structural modeling supports the\n                      <jats:italic>in silico<\/jats:italic>\n                      plausibility of TCDD engaging CXCR2, while transcriptomic concordance and keratinocyte qRT\u2013PCR findings support dysregulation of several core genes in epidermal cells. Baseline MMP9 was associated with week-12 treatment response in biologic-therapy cohorts. Nevertheless, the link between environmental TCDD exposure and psoriasis remains inferential because the study relied mainly on\n                      <jats:italic>in silico<\/jats:italic>\n                      analyses without individual-level exposure data; therefore, further validation in well-designed cohort studies is needed.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1816748","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:44:55Z","timestamp":1780029895000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated systems toxicology identifies TCDD-responsive targets linked to immune dysregulation and treatment response in psoriasis"],"prefix":"10.3389","volume":"13","author":[{"given":"Xuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Dermatology, Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yankun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"He","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41572-025-00630-5","article-title":"Psoriasis.","volume":"11","author":"Armstrong","year":"2025","journal-title":"Nat Rev Dis Primers."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1573905","DOI":"10.3389\/fimmu.2025.1573905","article-title":"Interventions in cytokine signaling: novel horizons for psoriasis treatment.","volume":"16","author":"Li","year":"2025","journal-title":"Front Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1694066","DOI":"10.3389\/fimmu.2025.1694066","article-title":"Keratinocytes as active regulators of cutaneous and mucosal immunity: a systematic review across inflammatory epithelial disorders.","volume":"16","author":"Klimitz","year":"2025","journal-title":"Front Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1038\/s42003-024-06700-w","article-title":"p38alpha deficiency ameliorates psoriasis development by downregulating STAT3-mediated keratinocyte proliferation and cytokine production.","volume":"7","author":"Zheng","year":"2024","journal-title":"Commun Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"461","DOI":"10.2147\/NDT.S403854","article-title":"Literature overview of the relation between psoriasis and alzheimer.","volume":"19","author":"Yang","year":"2023","journal-title":"Neuropsychiatr Dis Treat."},{"key":"B6","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s12920-023-01507-w","article-title":"Identification immune response genes in psoriasis after treatment with secukinumab.","volume":"16","author":"Wang","year":"2023","journal-title":"BMC Med Genomics."},{"key":"B7","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1001\/jamadermatol.2021.6019","article-title":"Association between short-term exposure to environmental air pollution and psoriasis flare.","volume":"158","author":"Bellinato","year":"2022","journal-title":"JAMA Dermatol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e05333","DOI":"10.2903\/j.efsa.2018.5333","article-title":"Risk for animal and human health related to the presence of dioxins and dioxin-like PCBs in feed and food.","volume":"16","author":"Knutsen","year":"2018","journal-title":"EFSA J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1243192","DOI":"10.3389\/ftox.2023.1243192","article-title":"Development of skin diseases following systemic exposure: example of dioxins.","volume":"5","author":"Sorg","year":"2023","journal-title":"Front Toxicol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.scitotenv.2014.11.026","article-title":"Environmental fate and dietary exposures of humans to TCDD as a result of the spraying of agent orange in upland forests of Vietnam.","author":"Armitage","year":"2015","journal-title":"Sci Total Environ."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3176","DOI":"10.3390\/cells10113176","article-title":"Role of AHR ligands in skin homeostasis and cutaneous inflammation.","volume":"10","author":"Fernandez-Gallego","year":"2021","journal-title":"Cells."},{"key":"B12","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jdermsci.2013.09.001","article-title":"Induction of a chloracne phenotype in an epidermal equivalent model by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is dependent on aryl hydrocarbon receptor activation and is not reproduced by aryl hydrocarbon receptor knock down.","volume":"73","author":"Forrester","year":"2014","journal-title":"J Dermatol Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1177\/12034754241239050","article-title":"The role of Aryl hydrocarbon receptor in the pathogenesis and treatment of psoriasis.","volume":"28","author":"Lin","year":"2024","journal-title":"J Cutan Med Surg."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies.","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","article-title":"Regression shrinkage and selection via the lasso.","volume":"58","author":"Tibshirani","year":"1996","journal-title":"J R Stat Soc Ser B."},{"key":"B16","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1023\/A:1012487302797","article-title":"Gene selection for cancer classification using support vector machines.","volume":"46","author":"Guyon","year":"2002","journal-title":"Mach Learn."},{"key":"B17","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles.","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.2147\/CCID.S484034","article-title":"Single-Cell sequencing combined with transcriptome sequencing to explore the molecular mechanisms related to psoriasis.","volume":"17","author":"Cailing","year":"2024","journal-title":"Clin Cosmet Investig Dermatol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility.","volume":"30","author":"Morris","year":"2009","journal-title":"J Comput Chem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.","volume":"31","author":"Trott","year":"2010","journal-title":"J Comput Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers.","author":"Abraham","year":"2015","journal-title":"SoftwareX."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field.","volume":"25","author":"Wang","year":"2004","journal-title":"J Comput Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"10269","DOI":"10.1021\/j100142a004","article-title":"A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model.","volume":"97","author":"Bayly","year":"1993","journal-title":"J Phys Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water.","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J Chem Phys."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1002\/jcc.23354","article-title":"CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data.","volume":"34","author":"Huang","year":"2013","journal-title":"J Comput Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1016\/j.chembiol.2014.09.001","article-title":"Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.","volume":"21","author":"Arkin","year":"2014","journal-title":"Chem Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s12551-016-0247-1","article-title":"Software for molecular docking: a review.","volume":"9","author":"Pagadala","year":"2017","journal-title":"Biophys Rev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"14633","DOI":"10.3390\/ijms241914633","article-title":"Regulatory mechanism of the IL-33-IL-37 axis via Aryl hydrocarbon receptor in atopic dermatitis and psoriasis.","volume":"24","author":"Tsuji","year":"2023","journal-title":"Int J Mol Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e20230683","DOI":"10.1084\/jem.20230683","article-title":"TCR signaling induces STAT3 phosphorylation to promote TH17 cell differentiation.","volume":"221","author":"Qin","year":"2024","journal-title":"J Exp Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"4846","DOI":"10.1038\/s41467-025-60174-w","article-title":"Alveolar epithelial and vascular CXCR2 mediates transcytosis of CXCL1 in inflamed lungs.","volume":"16","author":"Thomas","year":"2025","journal-title":"Nat Commun."},{"key":"B31","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/j.jid.2020.07.028","article-title":"Neutrophils enhance cutaneous vascular dilation and permeability to aggravate psoriasis by releasing matrix metallopeptidase 9.","volume":"141","author":"Chen","year":"2021","journal-title":"J Invest Dermatol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/1471-2121-10-27","article-title":"Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9.","volume":"10","author":"Peng","year":"2009","journal-title":"BMC Cell Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"8165","DOI":"10.2147\/JIR.S481835","article-title":"RNA sequencing reveals that the genes related to cell cycle and glycolysis play an essential role in IL-27-induced keratinocyte hyperproliferation.","volume":"17","author":"Wu","year":"2024","journal-title":"J Inflamm Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"9916","DOI":"10.1021\/acs.jmedchem.3c00769","article-title":"Fluorescent ligands enable target engagement studies for the intracellular allosteric binding site of the chemokine receptor CXCR2.","volume":"66","author":"Huber","year":"2023","journal-title":"J Med Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e15781","DOI":"10.1371\/journal.pone.0015781","article-title":"A self-propagating matrix metalloprotease-9 (MMP-9) dependent cycle of chronic neutrophilic inflammation.","volume":"6","author":"Xu","year":"2011","journal-title":"PLoS One."},{"key":"B36","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1016\/j.jid.2020.09.006","article-title":"MMP-9 mediates cross-talk between neutrophils and endothelial cells in psoriasis.","volume":"141","author":"Alves-Filho","year":"2021","journal-title":"J Invest Dermatol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1816748\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:45:01Z","timestamp":1780029901000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1816748\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":36,"alternative-id":["10.3389\/fmed.2026.1816748"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1816748","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]},"article-number":"1816748"}}