{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:43:41Z","timestamp":1789055021408,"version":"build-2803163510"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"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. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In recent years, growing attention has been paid to the role of Benzo [a]pyrene (BaP) in the development and progression of prostate cancer (PCa). However, the specific molecular mechanisms remain unclear. This study aims to explore the potential association between BaP and PCa and to identify key molecular targets that may underlie this relationship, using an integrative bioinformatics approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study initiated with a computational toxicology assessment of BaP\u2019s carcinogenicity and endocrine-disrupting properties using the ProTox 3.0 platform. Subsequently, potential target genes linking BaP to PCa were identified by integrating multiple public databases. The overlapping genes underwent PPI network construction and visualization, followed by GO functional annotation and KEGG pathway enrichment analyses to elucidate the underlying biological mechanisms. Through screening 101 machine learning algorithm combinations, we identified the most relevant key genes associated with PCa progression. Molecular docking technology was then employed to evaluate the binding interactions between BaP\/natural active products and these key targets. The CIBERSORT algorithm was utilized to analyze RRM2\u2019s regulatory role in the PCa tumor microenvironment, complemented by pan-cancer analysis to investigate RRM2\u2019s universal functions across various malignancies. Finally,\n                      <jats:italic>in vitro<\/jats:italic>\n                      cell experiments were conducted for validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      This study further underscores the carcinogenic properties and endocrine-disrupting effects of BaP. Integration of multi-source databases identified 443 potential BaP-PCa targets. GO and KEGG enrichment analyses revealed that these targets are primarily involved in regulating cell proliferation, inflammatory responses, oxidative stress, and multiple oncogenic signaling pathways. Machine learning algorithm screening showed that the Enet (\u03b1 = 0.1) model exhibited the best predictive performance and robustness. Through molecular docking, Kaplan-Meier survival analysis, and validation using the Human Protein Atlas (HPA) database, RRM2 was identified as a key regulatory gene and found to play a central role in BaP-mediated immunosuppression processes. Pan-cancer analysis demonstrated that RRM2 has universal functions across various malignancies. Molecular docking results indicated that seven known anti-tumor natural products exhibit significant binding affinity with RRM2.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments demonstrated that BaP treatment was associated with increased RRM2 expression in prostate cancer cells, while baicalin treatment reduced this effect, providing preliminary experimental support for the bioinformatic predictions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study delineates a potential mechanistic framework by which BaP may be associated with PCa progression through multi-target and multi-pathway mechanisms, highlighting RRM2 as a candidate core mediator. These findings provide a theoretical foundation for future experimental validation and epidemiological studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1768139","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:40:13Z","timestamp":1774593613000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Multi omics network toxicology and in vitro experiments elucidate the role of benzo [a] pyrene in prostate cancer"],"prefix":"10.3389","volume":"14","author":[{"given":"Zhenwei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology, Hechi Traditional Chinese Medicine Hospital","place":["Hechi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Ren","sequence":"additional","affiliation":[{"name":"Endocrinology Department, Hechi Traditional Chinese Medicine Hospital","place":["Hechi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanchang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, Hechi Traditional Chinese Medicine Hospital","place":["Hechi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guofu","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Urology, Hechi Traditional Chinese Medicine Hospital","place":["Hechi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"124650","DOI":"10.1016\/j.envpol.2024.124650","article-title":"Long-term spatiotemporal variation of benzo[a]pyrene in Japan: significant decrease in ambient concentrations, human exposure, and health risk","volume":"360","author":"Araki","year":"2024","journal-title":"Environ. Pollut."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1038\/onc.2014.155","article-title":"Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies","volume":"34","author":"Aye","year":"2015","journal-title":"Oncogene"},{"key":"B3","doi-asserted-by":"publisher","first-page":"6348","DOI":"10.3390\/ijms23116348","article-title":"Benzo[a]pyrene-Environmental occurrence, human exposure, and mechanisms of toxicity","volume":"23","author":"Bukowska","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1186\/s13578-023-01157-6","article-title":"The key cellular senescence related molecule RRM2 regulates prostate cancer progression and resistance to docetaxel treatment","volume":"13","author":"Cheng","year":"2023","journal-title":"Cell Biosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3681","DOI":"10.1038\/s41388-019-0688-7","article-title":"Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8\/miR21 axis","volume":"38","author":"Comito","year":"2019","journal-title":"Oncogene"},{"key":"B6","doi-asserted-by":"publisher","first-page":"216308","DOI":"10.1016\/j.canlet.2023.216308","article-title":"Inhibition of RRM2 radiosensitizes glioblastoma and uncovers synthetic lethality in combination with targeting CHK1","volume":"570","author":"Corrales-Guerrero","year":"2023","journal-title":"Cancer Lett."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e1004362","DOI":"10.1371\/journal.pmed.1004362","article-title":"Risk factors for prostate cancer: an umbrella review of prospective observational studies and mendelian randomization analyses","volume":"21","author":"Cui","year":"2024","journal-title":"PLoS Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1186\/s13046-023-02774-2","article-title":"LncRNA SNHG4 promotes prostate cancer cell survival and resistance to enzalutamide through a let-7a\/RREB1 positive feedback loop and a ceRNA network","volume":"42","author":"Dong","year":"2023","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"110864","DOI":"10.1016\/j.isci.2024.110864","article-title":"RRM2 promotes liver metastasis of pancreatic cancer by stabilizing YBX1 and activating the TGF-Beta pathway","volume":"27","author":"Du","year":"2024","journal-title":"iScience"},{"key":"B10","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/s41585-025-01031-9","article-title":"Endocrine-disrupting chemicals as prostate carcinogens","volume":"22","author":"Feij\u00f3","year":"2025","journal-title":"Nat. Rev. Urol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1080\/19338244.2024.2394418","article-title":"Apigenin ameliorates petrol vapors-induced oxidative stress as occupational and environmental pollutants in rats: an in vivo study","volume":"79","author":"Ghahri","year":"2024","journal-title":"Arch. Environ. Occup. Health"},{"key":"B12","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/s41585-019-0193-3","article-title":"A new era: artificial intelligence and machine learning in prostate cancer","volume":"16","author":"Goldenberg","year":"2019","journal-title":"Nat. Rev. Urol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1146\/annurev-biochem-013118-111843","article-title":"Ribonucleotide reductases: structure, chemistry, and metabolism suggest new therapeutic targets","volume":"89","author":"Greene","year":"2020","journal-title":"Annu. Rev. Biochem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"118601","DOI":"10.1016\/j.ecoenv.2025.118601","article-title":"Multi-omics network toxicology reveals the role of benzo[a]pyrene in ovarian cancer: integrating gut microbiota dynamics and Mendelian randomization","volume":"302","author":"Huang","year":"2025","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B15","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.fct.2018.03.003","article-title":"Pharmacokinetics of [C]-Benzo[a]pyrene (BaP) in humans: impact of Co-Administration of smoked salmon and BaP dietary restriction","volume":"115","author":"Hummel","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.canlet.2022.01.015","article-title":"Tumor microenvironment mechanisms and bone metastatic disease progression of prostate cancer","volume":"530","author":"Kang","year":"2022","journal-title":"Cancer Lett."},{"key":"B17","first-page":"5443","article-title":"Characteristics of the immune microenvironment associated with RRM2 expression and its application to PD-L1\/PD-1 inhibitors in lung adenocarcinoma","volume":"13","author":"Lee","year":"2023","journal-title":"Am. J. Cancer Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e14432","DOI":"10.7717\/peerj.14432","article-title":"A pan-cancer analysis of the oncogenic role of ribonucleotide reductase subunit M2 in human tumors","volume":"10","author":"Li","year":"2022","journal-title":"PeerJ"},{"key":"B19","doi-asserted-by":"publisher","first-page":"117966","DOI":"10.1016\/j.ecoenv.2025.117966","article-title":"Air pollution and prostate cancer: unraveling the connection through network toxicology and machine learning","volume":"292","author":"Li","year":"2025","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4480","DOI":"10.1158\/1078-0432.CCR-18-4046","article-title":"A novel mechanism driving poor-prognosis prostate cancer: overexpression of the DNA repair gene, ribonucleotide reductase small subunit M2 (RRM2)","volume":"25","author":"Mazzu","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1002\/1878-0261.12706","article-title":"Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer","volume":"14","author":"Mazzu","year":"2020","journal-title":"Mol. Oncol."},{"key":"B22","first-page":"241","article-title":"In vivo and in vitro effect of baicalein on human prostate cancer cells","volume":"26","author":"Miocinovic","year":"2005","journal-title":"Int. J. Oncol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1007\/s40618-022-01983-4","article-title":"Endocrine-disrupting chemicals (EDCs) and cancer: new perspectives on an old relationship","volume":"46","author":"Modica","year":"2023","journal-title":"J. Endocrinol. Invest"},{"key":"B24","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":"B25","doi-asserted-by":"publisher","first-page":"e262","DOI":"10.1016\/S1470-2045(19)30149-4","article-title":"Big data and machine learning algorithms for health-care delivery","volume":"20","author":"Ngiam","year":"2019","journal-title":"Lancet Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3390\/ijerph2007010002","article-title":"Induction of cell death, DNA strand breaks, and cell cycle arrest in DU145 human prostate carcinoma cell line by benzo[a]pyrene and benzo[a]pyrene-7,8-diol-9,10-epoxide","volume":"4","author":"Nwagbara","year":"2007","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B27","doi-asserted-by":"publisher","first-page":"101032","DOI":"10.1016\/j.neo.2024.101032","article-title":"Epitranscriptomic mechanisms of androgen signalling and prostate cancer","volume":"56","author":"Patke","year":"2024","journal-title":"Neoplasia"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1001\/jama.2025.0228","article-title":"Prostate cancer: a review","volume":"333","author":"Raychaudhuri","year":"2025","journal-title":"JAMA"},{"key":"B29","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.mrrev.2017.08.003","article-title":"Inflammation and the chemical carcinogen benzo[a]pyrene: partners in crime","volume":"774","author":"Shi","year":"2017","journal-title":"Mutat. Res. Rev. Mutat. Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"124675","DOI":"10.1016\/j.envpol.2024.124675","article-title":"Multi-omics integration analysis: tools and applications in environmental toxicology","volume":"360","author":"Shi","year":"2024","journal-title":"Environ. Pollut."},{"key":"B31","doi-asserted-by":"publisher","first-page":"203","DOI":"10.3322\/caac.21830","article-title":"J clin","volume":"74","author":"Siegel","year":"2024"},{"key":"B32","doi-asserted-by":"publisher","first-page":"112442","DOI":"10.1016\/j.biopha.2021.112442","article-title":"Therapeutic potential of flavonoids in cancer: ROS-Mediated mechanisms","volume":"146","author":"Slika","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B33","doi-asserted-by":"publisher","first-page":"108872","DOI":"10.1016\/j.clim.2021.108872","article-title":"Identification of critical ferroptosis regulators in lung adenocarcinoma that RRM2 facilitates tumor immune infiltration by inhibiting ferroptotic death","volume":"232","author":"Tang","year":"2021","journal-title":"Clin. Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1101\/gad.315739.118","article-title":"Genetics and biology of prostate cancer","volume":"32","author":"Wang","year":"2018","journal-title":"Genes Dev."},{"key":"B35","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.jnutbio.2006.12.002","article-title":"Dietary PUFA and flavonoids as deterrents for environmental pollutants","volume":"18","author":"Watkins","year":"2007","journal-title":"J. Nutr. Biochem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e2100881","DOI":"10.1002\/advs.202100881","article-title":"RRM2 regulates sensitivity to sunitinib and PD-1 blockade in renal cancer by stabilizing ANXA1 and activating the AKT pathway","volume":"8","author":"Xiong","year":"2021","journal-title":"Adv. Sci. (Weinh)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2908","DOI":"10.1002\/tox.24157","article-title":"Integration of machine learning for developing a prognostic signature related to programmed cell death in colorectal cancer","volume":"39","author":"Xu","year":"2024","journal-title":"Environ. Toxicol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.envpol.2016.03.050","article-title":"Biological impact of environmental polycyclic aromatic hydrocarbons (ePAHs) as endocrine disruptors","volume":"213","author":"Zhang","year":"2016","journal-title":"Environ. Pollut."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1646623","DOI":"10.3389\/fnut.2025.1646623","article-title":"A comprehensive analysis reveals the relationship between artificial sweeteners and prostate cancer","volume":"12","author":"Zhang","year":"","journal-title":"Front. Nutr."},{"key":"B40","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.jes.2024.11.032","article-title":"Immunosuppressive role of benzo[a]pyrene exposure in prostate cancer progression","volume":"156","author":"Zhang","year":"","journal-title":"J. Environ. Sci. (China)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.gendis.2022.11.022","article-title":"Ribonucleotide reductase M2 (RRM2): regulation, function and targeting strategy in human cancer","volume":"11","author":"Zuo","year":"2022","journal-title":"Genes Dis."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1768139\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:40:16Z","timestamp":1774593616000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1768139\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":41,"alternative-id":["10.3389\/fcell.2026.1768139"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1768139","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]},"article-number":"1768139"}}