{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:17:46Z","timestamp":1793643466775,"version":"4.5.1"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"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. Mol. Biosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Di (2-ethylhexyl) phthalate (DEHP), the most widely used phthalate plasticizer, has been implicated in skin cancer. However, its key targets and multi-pathway mechanisms regulating skin cancer onset and progression remain unclear. Therefore, elucidating DEHP\u2019s molecular mechanisms in skin cancer development is crucial for prevention and intervention strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study integrates network toxicology, molecular docking, and experimental validation to systematically elucidate the mechanism by which DEHP induces skin cancer. Specifically, we predicted potential DEHP targets and skin cancer-associated targets (melanoma, squamous cell carcinoma, basal cell carcinoma) using multiple databases. Core targets were identified through CytoNCA topological analysis, MCODE module mining, and CytoHubba multi-algorithm integration. Performed GO\/KEGG enrichment analysis using the DAVID database; validated the binding potential between DEHP and core targets via molecular docking with AutoDock Vina; and finally verified the abnormal expression profiles of core targets through TCGA\/GTEx transcriptomic data, HPA proteomic data, and RT-qPCR experiments in A-375 (human malignant melanoma cells)\/Hacat cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Initially, this study identified 11 key DEHP-induced skin cancer targets: CTNNB1, ESR1, HIF1A, IL6, MTOR, MYC, STAT3, AKT1, BCL2, CASP3, and CCND1. These targets exhibited specific regulation across different skin cancer subtypes. Subsequently, a four-tier regulatory network linking \u201cDEHP-core targets-pathways-skin cancer\u201d was constructed. Molecular docking confirmed stable binding conformations between DEHP and all 11 key targets, while enrichment analysis revealed their associations with cellular proliferation, apoptosis, inflammatory responses, and core pathways including Jak-STAT and PI3K-Akt\/mTOR. Finally, transcriptomic, proteomic, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      cellular experiments validated the significant dysregulation of these targets in skin cancer tissues and tumor cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, this study systematically elucidates the toxicological mechanism by which DEHP promotes skin cancer development through subtype-specific pathways regulated by 11 key targets, clarifying its direct binding patterns with core targets and downstream pathway disruption characteristics. This not only fills a research gap in the molecular mechanisms of DEHP-induced skin carcinogenesis but also provides novel biomarkers for environmental exposure prevention and targeted interventions against skin cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmolb.2026.1841556","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:41:17Z","timestamp":1779338477000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Revealing key biomarkers and molecular mechanisms associated with di(2-ethylhexyl) phthalate in skin cancer"],"prefix":"10.3389","volume":"13","author":[{"given":"Haidong","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Burn Plastic and Wound Repair Surgery, Key Laboratory of Clinical Cohort Research on Bone and Joint Degenerative Diseases of Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities","place":["Baise, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical School, Nanjing University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangqi","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Burn Plastic and Wound Repair Surgery, Key Laboratory of Clinical Cohort Research on Bone and Joint Degenerative Diseases of Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities","place":["Baise, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huade","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Burn Plastic and Wound Repair Surgery, Key Laboratory of Clinical Cohort Research on Bone and Joint Degenerative Diseases of Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities","place":["Baise, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runze","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Burn Plastic and Wound Repair Surgery, Key Laboratory of Clinical Cohort Research on Bone and Joint Degenerative Diseases of Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities","place":["Baise, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingpeng","family":"Ban","sequence":"additional","affiliation":[{"name":"Department of Burn Plastic and Wound Repair Surgery, Key Laboratory of Clinical Cohort Research on Bone and Joint Degenerative Diseases of Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities","place":["Baise, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Burn Plastic and Wound Repair Surgery, Key Laboratory of Clinical Cohort Research on Bone and Joint Degenerative Diseases of Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities","place":["Baise, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonghua","family":"Sun","sequence":"additional","affiliation":[{"name":"Medical School, Nanjing University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihua","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Burn Plastic and Wound Repair Surgery, Key Laboratory of Clinical Cohort Research on Bone and Joint Degenerative Diseases of Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities","place":["Baise, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dapeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Burn Plastic and Wound Repair Surgery, Key Laboratory of Clinical Cohort Research on Bone and Joint Degenerative Diseases of Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities","place":["Baise, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"125203","DOI":"10.1016\/j.ijpharm.2025.125203","article-title":"Recent advances in lipid-based nanocarriers for advanced skin cancer therapy","volume":"670","author":"Ali","year":"2025","journal-title":"Int. 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