{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:54:45Z","timestamp":1790675685932,"version":"4.1.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"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. Toxicol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Human evidence linking di(2-ethylhexyl) phthalate (DEHP) exposure to hepatocellular carcinoma (HCC) is limited, and it remains unclear whether DEHP-relevant detoxification biology captures clinically meaningful HCC heterogeneity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated two-sample Mendelian randomization, proteomic and phosphoproteomic subtyping, bulk, single-cell and spatial transcriptomics, computational candidate prioritization, molecular docking, and cell-based assays. Genetically proxied MECPP and MEHHP were evaluated for associations with HCC and liver-related outcomes. DPTS-related molecular, cellular, spatial, and experimental patterns were then characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MR did not support a causal association of genetically proxied MECPP or MEHHP with HCC. In 165 CPTAC tumors, consensus clustering identified two detoxification-phosphorylation tumor subtypes. Compared with DPTS1, DPTS2 showed coordinated suppression of xenobiotic metabolism, bile acid metabolism, fatty-acid oxidation, phase II conjugation, and transport programs. A transcriptomically projected DPTS2-like state was associated with poorer overall survival in TCGA-LIHC, but this association was not replicated in ICGC-LIRI-JP. Single-cell and spatial analyses localized these programs mainly to hepatocyte-like compartments and showed modest spatial coordination with nine prioritized genes, including ALDH2, EHHADH, and PCK2. LINCS-based screening and molecular docking prioritized PD-0325901, trametinib, and regorafenib, but these predictions did not demonstrate binding or efficacy, and the compounds were not tested experimentally. Basal qPCR and DEHP-treatment experiments showed cell-line-specific expression and phenotypic responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>DPTS defines a DEHP-relevant, detoxification-suppressed HCC molecular phenotype rather than an exposure-defined or DEHP-induced subtype. These findings provide a bounded framework for future mechanistic validation of metabolic vulnerability in HCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/ftox.2026.1925431","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:54:36Z","timestamp":1790672076000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic evidence and multi-omics characterization of DEHP-relevant detoxification and metabolic heterogeneity in hepatocellular carcinoma"],"prefix":"10.3389","volume":"8","author":[{"given":"Zeyang","family":"Fan","sequence":"first","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letian","family":"Ren","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wence","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]},{"name":"Department of General Surgery, The Second Hospital of Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet. Epidemiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.1002\/hep.32740","article-title":"The liver cancer immune microenvironment: therapeutic implications for hepatocellular carcinoma","volume":"77","author":"Donne","year":"2023","journal-title":"Hepatology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock vina 1.2.0: new docking methods, expanded force field, and python bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model"},{"key":"B5","doi-asserted-by":"publisher","first-page":"113773","DOI":"10.1016\/j.celrep.2024.113773","article-title":"THBS1(+) myeloid cells expand in SLD hepatocellular carcinoma and contribute to immunosuppression and unfavorable prognosis through TREM1","volume":"43","author":"Giraud","year":"2024","journal-title":"Cell Rep."},{"key":"B6","doi-asserted-by":"publisher","first-page":"121186","DOI":"10.1016\/j.envres.2025.121186","article-title":"Association between phthalate exposure and metabolic dysfunction-associated steatotic liver disease (MASLD) - systematic literature review","volume":"273","author":"Gogola","year":"2025","journal-title":"Environ. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1830","DOI":"10.1200\/JCO.23.02745","article-title":"Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline update","volume":"42","author":"Gordan","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"113968","DOI":"10.1016\/j.fct.2023.113968","article-title":"Association between Di-2-ethylhexyl phthalate and nonalcoholic fatty liver disease among US adults: mediation analysis of body mass index and waist circumference in the NHANES","volume":"179","author":"He","year":"2023","journal-title":"Food Chem. Toxicol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2309","DOI":"10.1007\/s10753-022-01694-1","article-title":"ALDH2 hampers immune escape in liver hepatocellular carcinoma through ROS\/Nrf2-mediated autophagy","volume":"45","author":"Hu","year":"2022","journal-title":"Inflammation"},{"key":"B10","doi-asserted-by":"publisher","first-page":"113119","DOI":"10.1016\/j.fct.2022.113119","article-title":"Di-2-ethylhexyl phthalate (DEHP) induced lipid metabolism disorder in liver via activating the LXR\/SREBP-1c\/PPAR\u03b1\/\u03b3 and NF-\u03baB signaling pathway","volume":"165","author":"Huang","year":"2022","journal-title":"Food Chem. Toxicol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"S228","DOI":"10.3350\/cmh.2024.0824","article-title":"Hepatocellular carcinoma: updates on epidemiology, surveillance, diagnosis and treatment","volume":"31","author":"Hwang","year":"2025","journal-title":"Clin. Mol. Hepatol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1007\/s12199-013-0362-6","article-title":"Species and inter-individual differences in metabolic capacity of di(2-ethylhexyl)phthalate (DEHP) between human and mouse livers","volume":"19","author":"Ito","year":"2014","journal-title":"Environ. Health Prev. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"4913","DOI":"10.1093\/eurheartj\/ehad736","article-title":"Mendelian randomization for cardiovascular diseases: principles and applications","volume":"44","author":"Larsson","year":"2023","journal-title":"Eur. Heart J."},{"key":"B14","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1002\/cac2.12536","article-title":"Positive regulation of cell proliferation by the miR-1290-EHHADH axis in hepatocellular carcinoma","volume":"44","author":"Lee","year":"2024","journal-title":"Cancer Commun. (Lond)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1097\/HEP.0000000000000553","article-title":"Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma","volume":"79","author":"Li","year":"","journal-title":"Hepatology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"14051","DOI":"10.1038\/s41598-024-64907-7","article-title":"Association of mitochondrial phosphoenolpyruvate carboxykinase with prognosis and immune regulation in hepatocellular carcinoma","volume":"14","author":"Li","year":"","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.jhep.2023.01.011","article-title":"Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy","volume":"78","author":"Liu","year":"2023","journal-title":"J. Hepatol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"4594","DOI":"10.1038\/s41467-022-32283-3","article-title":"A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma","volume":"13","author":"Lu","year":"2022","journal-title":"Nat. Commun."},{"key":"B19","doi-asserted-by":"publisher","first-page":"D672","DOI":"10.1093\/nar\/gkad1025","article-title":"The reactome pathway knowledgebase 2024","volume":"52","author":"Milacic","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"B20","first-page":"1","article-title":"Carcinogenesis bioassay of Di(2-ethylhexyl)phthalate (CAS no. 117-81-7) in F344 rats and B6C3F1 mice (feed studies)","volume":"217","year":"1982","journal-title":"Natl. Toxicol. Program Tech. Rep. Ser."},{"key":"B21","article-title":"Di(2-ethylhexyl) phthalate: CAS no. 117-81-7","volume-title":"15th Report on Carcinogens","year":""},{"key":"B22","article-title":"NTP technical report on the toxicology and carcinogenesis studies of Di(2-ethylhexyl) phthalate (CASRN 117-81-7) administered in feed to sprague dawley rats","year":""},{"key":"B23","doi-asserted-by":"publisher","first-page":"e2305374","DOI":"10.1002\/advs.202305374","article-title":"Metabolic enzyme SLC27A5 regulates PIP4K2A pre-mRNA splicing as a noncanonical mechanism to suppress hepatocellular carcinoma metastasis","volume":"11","author":"Nie","year":"2024","journal-title":"Adv. Sci. (Weinh)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1038\/s12276-025-01415-2","article-title":"Metabolic reprogramming in hepatocellular carcinoma: mechanisms and therapeutic implications","volume":"57","author":"Park","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1038\/s43018-024-00824-y","article-title":"Spatial single-cell protein landscape reveals vimentin(high) macrophages as immune-suppressive in the microenvironment of hepatocellular carcinoma","volume":"5","author":"Qiu","year":"2024","journal-title":"Nat. Cancer"},{"key":"B26","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"B27","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.mrrev.2011.12.004","article-title":"Mechanistic considerations for human relevance of cancer hazard of di(2-ethylhexyl) phthalate","volume":"750","author":"Rusyn","year":"2012","journal-title":"Mutat. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1080\/10408440600779065","article-title":"Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver","volume":"36","author":"Rusyn","year":"2006","journal-title":"Crit. Rev. Toxicol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"6207","DOI":"10.1038\/srep06207","article-title":"Critical limitations of consensus clustering in class discovery","volume":"4","author":"\u0218enbabao\u011flu","year":"2014","journal-title":"Sci. Rep."},{"key":"B30","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13045-024-01549-2","article-title":"Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives","volume":"17","author":"Shen","year":"2024","journal-title":"J. Hematol. Oncol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e70043","DOI":"10.3322\/caac.70043","article-title":"Cancer statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. Clin."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR statement","volume":"326","author":"Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"B33","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/bs.pmch.2021.01.004","article-title":"Use of molecular docking computational tools in drug discovery","volume":"60","author":"Stanzione","year":"2021","journal-title":"Prog. Med. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B35","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1053\/j.gastro.2023.01.033","article-title":"Global epidemiology and genetics of hepatocellular carcinoma","volume":"164","author":"Toh","year":"2023","journal-title":"Gastroenterology"},{"key":"B36","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":"B37","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1093\/bioinformatics\/btq170","article-title":"ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking","volume":"26","author":"Wilkerson","year":"2010","journal-title":"Bioinformatics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"101315","DOI":"10.1016\/j.xcrm.2023.101315","article-title":"Integrated omics landscape of hepatocellular carcinoma suggests proteomic subtypes for precision therapy","volume":"4","author":"Xing","year":"2023","journal-title":"Cell Rep. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41419-023-05558-w","article-title":"SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase","volume":"14","author":"Xu","year":"2023","journal-title":"Cell Death Dis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1016\/j.apsb.2021.02.008","article-title":"The role of ALDH2 in tumorigenesis and tumor progression: targeting ALDH2 as a potential cancer treatment","volume":"11","author":"Zhang","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"B41","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s13073-023-01218-y","article-title":"Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence","volume":"15","author":"Zhang","year":"2023","journal-title":"Genome Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"840287","DOI":"10.3389\/fonc.2022.840287","article-title":"ABCC6 knockdown fuels cell proliferation by regulating PPAR\u03b1 in hepatocellular carcinoma","volume":"12","author":"Zhao","year":"2022","journal-title":"Front. Oncol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"178285","DOI":"10.1016\/j.scitotenv.2024.178285","article-title":"The role of di-(2-ethylhexyl) phthalate in cancer initiation and progression: mechanisms and health implications","volume":"959","author":"Zhou","year":"2025","journal-title":"Sci. Total Environ."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1407976","DOI":"10.3389\/fpubh.2024.1407976","article-title":"Association between phthalates exposure and non-alcoholic fatty liver disease under different diagnostic criteria: a cross-sectional study based on NHANES 2017 to 2018","volume":"12","author":"Zou","year":"2024","journal-title":"Front. Public Health"},{"key":"B45","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.ajhg.2022.04.001","article-title":"Combining evidence from Mendelian randomization and colocalization: review and comparison of approaches","volume":"109","author":"Zuber","year":"2022","journal-title":"Am. J. Hum. Genet."}],"container-title":["Frontiers in Toxicology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1925431\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:54:37Z","timestamp":1790672077000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1925431\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":45,"alternative-id":["10.3389\/ftox.2026.1925431"],"URL":"https:\/\/doi.org\/10.3389\/ftox.2026.1925431","relation":{},"ISSN":["2673-3080"],"issn-type":[{"value":"2673-3080","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"article-number":"1925431"}}