{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T05:46:49Z","timestamp":1782539209104,"version":"3.54.5"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2024YFF0728801"],"award-info":[{"award-number":["2024YFF0728801"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Bisphenol A (BPA) is a common industrial chemical primarily used in the manufacture of plastics, and it has been found in more than 90% of people worldwide. As an endocrine disruptor, BPA can impair reproduction, development, immunity, metabolism, and cognition; it also disturbs immune balance and thus fosters chronic inflammation. A number of population-based studies have indicated a link between environmental BPA exposure and atopic dermatitis (AD). Nevertheless, the detailed molecular pathways connecting BPA to AD remain poorly understood. AD is the leading chronic recurrent inflammatory skin disorder, characterized by severe itching and repeated eczema-like lesions. Its prevalence is roughly 13% among children and 5% among adults, and its global incidence continues to rise, imposing heavy health and economic burdens on societies. To clarify whether and how BPA may promote or worsen AD, we carried out a comprehensive computational study that integrated network toxicology, transcriptomic data, machine learning, molecular docking, and molecular dynamics simulations. From the CTD, ChEMBL, and SwissTargetPrediction databases, we collected 5701 potential BPA targets; from GeneCards and OMIM, we obtained 3270 genes linked to AD. The overlap between these two gene sets gave a group of common candidate genes. Enrichment analyses using GO and KEGG showed that these common genes were significantly overrepresented in the PI3K-Akt signaling pathway, Th17 cell differentiation, and the JAK-STAT signaling pathway\u2014all central to immune and inflammatory regulation. We then built a protein\u2013protein interaction (PPI) network by submitting the common genes to the STRING database and employed Cytoscape to extract hub genes from that network. By integrating human AD transcriptomic profiles with the hub genes and applying two machine learning techniques (LASSO and SVM), we identified six core toxic targets of BPA in AD: TIGIT, JAK3, IL22, S100A8, CCL2, and FCER1G. These six targets fall into two main functional categories: immune dysregulation and inflammatory cell infiltration. Subsequent molecular docking and molecular dynamics simulation experiments confirmed that BPA binds well to all six targets and can form stable complexes with them. Collectively, our findings offer a preliminary experimental foundation for future investigations into the pathogenesis of BPA-induced AD and provide important molecular evidence for understanding how environment\u2013gene interactions contribute to complex inflammatory skin diseases such as AD.<\/jats:p>","DOI":"10.3390\/cimb48070652","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T08:14:12Z","timestamp":1782375252000},"page":"652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Network Toxicology and Machine Learning Uncover BPA-Driven Molecular Mechanisms in Atopic Dermatitis"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0167-4288","authenticated-orcid":false,"given":"Xingxin","family":"Cao","sequence":"first","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangkai","family":"Cai","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxue","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Jin","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengmei","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suqin","family":"Duan","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanlong","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108575","DOI":"10.1016\/j.envres.2019.108575","article-title":"The adverse health effects of bisphenol A and related toxicity mechanisms","volume":"176","author":"Ma","year":"2019","journal-title":"Environ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3390\/jox12030015","article-title":"Endocrine-Disrupting Effects of Bisphenol A on the Cardiovascular System: A Review","volume":"12","author":"Fonseca","year":"2022","journal-title":"J. Xenobiot."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s12940-025-01169-4","article-title":"Maternal urinary concentrations of bisphenol A during pregnancy and birth size in children from the Odense Child Cohort","volume":"24","author":"Beck","year":"2025","journal-title":"Environ. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"126819","DOI":"10.1016\/j.chemosphere.2020.126819","article-title":"Bisphenol A induces DNA damage in cells exerting immune surveillance functions at peripheral and central level","volume":"254","author":"Viggiano","year":"2020","journal-title":"Chemosphere"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"112987","DOI":"10.1016\/j.ecoenv.2021.112987","article-title":"Prenatal exposure to bisphenols, immune responses in cord blood and infantile eczema: A nested prospective cohort study in China","volume":"228","author":"Li","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kim, S.H., Yu, S.Y., Choo, J.H., Kim, J., Ahn, K., and Hwang, S.Y. (2024). Epigenetic Methylation Changes in Pregnant Women: Bisphenol Exposure and Atopic Dermatitis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031579"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/cod.14688","article-title":"Incidence of allergic contact dermatitis in Finland 1998\u20132021: A nationwide registry-based study","volume":"92","author":"Sinikumpu","year":"2025","journal-title":"Contact Dermat."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"124786","DOI":"10.1016\/j.carbpol.2025.124786","article-title":"Hyaluronic acid-butyrate conjugates for barrier restoration in atopic dermatitis: CD44-mediated retention and inflammation-responsive release","volume":"375","author":"Liu","year":"2026","journal-title":"Carbohydr. Polym."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"116429","DOI":"10.1016\/j.ecoenv.2024.116429","article-title":"Air pollution and skin diseases: A comprehensive evaluation of the associated mechanism","volume":"278","author":"Gu","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jep.2012.09.051","article-title":"Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease","volume":"145","author":"Tao","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"125708","DOI":"10.1016\/j.jenvman.2025.125708","article-title":"Exploring the toxicological impact of bisphenol a exposure on psoriasis through network toxicology, machine learning, and multi-dimensional bioinformatics analysis","volume":"385","author":"Feng","year":"2025","journal-title":"J. Environ. Manag."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Cao, X., Duan, S., Li, A., and He, Z. (2025). Astragalus in Acute Pancreatitis: Insights from Network Pharmacology, Molecular Docking, and Meta-Analysis Validation. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47050379"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Karim, M.R., Morshed, M.N., Iqbal, S., Mohammad, S., Mathiyalagan, R., Yang, D.C., Kim, Y.J., Song, J.H., and Yang, D.U. (2023). A Network Pharmacology and Molecular-Docking-Based Approach to Identify the Probable Targets of Short-Chain Fatty-Acid-Producing Microbial Metabolites against Kidney Cancer and Inflammation. Biomolecules, 13.","DOI":"10.3390\/biom13111678"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10688","DOI":"10.1038\/s41467-024-54559-6","article-title":"Immune modules to guide diagnosis and personalized treatment of inflammatory skin diseases","volume":"15","author":"Seremet","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e20231467","DOI":"10.1084\/jem.20231467","article-title":"Enhanced TLR7-dependent production of type I interferon by pDCs underlies pandemic chilblains","volume":"222","author":"Saidoune","year":"2025","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cao, X., Li, M., Xie, X., Feng, Z., Jin, W., Li, Y., Yang, F., Duan, S., and He, Z. (2025). Salvia miltiorrhiza for Viral Myocarditis: Multi-Computational Pharmacological Exploration and Meta-Analytic Efficacy Validation. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262311753"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/S0140-6736(15)00149-X","article-title":"Atopic dermatitis","volume":"387","author":"Weidinger","year":"2016","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"AAAAI\/ACAAI JTF Atopic Dermatitis Guideline Panel, Chu, D.K., Schneider, L., Asiniwasis, R.N., Boguniewicz, M., De Benedetto, A., Ellison, K., Frazier, W.T., Greenhawt, M., and Huynh, J. (2024). Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology\/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations. Ann. Allergy Asthma Immunol., 132, 274\u2013312.","DOI":"10.1016\/j.anai.2023.11.009"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.jaci.2025.01.013","article-title":"Update on atopic dermatitis","volume":"155","author":"Meledathu","year":"2025","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1093\/bjd\/ljaf451","article-title":"From prebiotics to engineered microbes: Microbe-inspired treatments for atopic dermatitis","volume":"194","author":"Nevot","year":"2026","journal-title":"Br. J. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"147953","DOI":"10.1016\/j.scitotenv.2021.147953","article-title":"Joint association of prenatal bisphenol-A and phthalates exposure with risk of atopic dermatitis in 6-month-old infants","volume":"789","author":"Lee","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s12940-017-0225-5","article-title":"Exposure to phthalates and bisphenol A are associated with atopic dermatitis symptoms in children: A time-series analysis","volume":"16","author":"Kim","year":"2017","journal-title":"Environ. Health"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1038\/s41590-025-02300-w","article-title":"The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells","volume":"26","author":"Panetti","year":"2025","journal-title":"Nat. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"112663","DOI":"10.1016\/j.intimp.2024.112663","article-title":"Novel insights into immune checkpoints in psoriasis and atopic dermatitis: From expression and function to treatments","volume":"139","author":"Liu","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"123393","DOI":"10.1016\/j.envpol.2024.123393","article-title":"Adverse effects of bisphenol A and its analogues on male fertility: An epigenetic perspective","volume":"345","author":"Deng","year":"2024","journal-title":"Environ. Pollut."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1038\/s41375-023-01911-2","article-title":"Characterization of immune exhaustion and suppression in the tumor microenvironment of splenic marginal zone lymphoma","volume":"37","author":"Anagnostou","year":"2023","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00281-009-0188-x","article-title":"Biology of interleukin-22","volume":"32","author":"Wolk","year":"2010","journal-title":"Semin. Immunopathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1038\/s41418-025-01504-9","article-title":"Chronic skin and systemic inflammation modulated by S100A8 and S100A9 complexes","volume":"32","author":"Bakiri","year":"2025","journal-title":"Cell Death Differ."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41392-021-00791-1","article-title":"The JAK\/STAT signaling pathway: From bench to clinic","volume":"6","author":"Hu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.alit.2021.10.004","article-title":"Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors","volume":"71","author":"Nakashima","year":"2022","journal-title":"Allergol. Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"111581","DOI":"10.1016\/j.intimp.2024.111581","article-title":"Radical S-adenosyl methionine domain-containing 2, a potential target of D-tryptophan in asthma treatment, regulates T helper cell type 1\/2 balance","volume":"129","author":"Wang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.cyto.2015.05.014","article-title":"IL-4 and IL-13 signaling in allergic airway disease","volume":"75","author":"Gour","year":"2015","journal-title":"Cytokine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.jaci.2023.10.034","article-title":"Similarities and differences in peripheral itch and pain pathways in atopic dermatitis","volume":"153","author":"Yosipovitch","year":"2024","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1111\/j.1398-9995.2011.02760.x","article-title":"Demethylation of the FCER1G promoter leads to Fc\u03b5RI overexpression on monocytes of patients with atopic dermatitis","volume":"67","author":"Liang","year":"2012","journal-title":"Allergy"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.jaci.2019.06.011","article-title":"Thymic stromal lymphopoietin epigenetically upregulates Fc receptor \u03b3 subunit-related receptors on antigen-presenting cells and induces TH2\/TH17 polarization through dectin-2","volume":"144","author":"Liang","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Liu, T., Li, S., Ying, S., Tang, S., Ding, Y., Li, Y., Qiao, J., and Fang, H. (2020). The IL-23\/IL-17 Pathway in Inflammatory Skin Diseases: From Bench to Bedside. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.594735"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.etap.2016.09.017","article-title":"Gestational and lactational exposure to low-dose bisphenol A increases Th17 cells in mice offspring","volume":"47","author":"Luo","year":"2016","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"114864","DOI":"10.1016\/j.bcp.2021.114864","article-title":"Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K\/AKT\/mTOR and MAPK signaling pathways","volume":"195","author":"Yu","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"117946","DOI":"10.1016\/j.ecoenv.2025.117946","article-title":"Bisphenol A exposure enhances proliferation and tumorigenesis of papillary thyroid carcinoma through ROS generation and activation of NOX4 signaling pathways","volume":"292","author":"Wang","year":"2025","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1016\/j.tiv.2015.09.002","article-title":"N-acetyl cysteine protects human oral keratinocytes from Bis-GMA-induced apoptosis and cell cycle arrest by inhibiting reactive oxygen species-mediated mitochondrial dysfunction and the PI3K\/Akt pathway","volume":"29","author":"Zhu","year":"2015","journal-title":"Toxicol. In Vitro"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/7\/652\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T05:08:08Z","timestamp":1782536888000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/7\/652"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":40,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cimb48070652"],"URL":"https:\/\/doi.org\/10.3390\/cimb48070652","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]}}}