{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:18:33Z","timestamp":1788218313849,"version":"build-2803163510"},"reference-count":95,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001412","name":"Council of Scientific and Industrial Research, India","doi-asserted-by":"publisher","award":["MLP21006"],"award-info":[{"award-number":["MLP21006"]}],"id":[{"id":"10.13039\/501100001412","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>CYP2J2 catalyzes the conversion of arachidonic acid into epoxyeicosatrienoic acids (EET), which have gained significant attention due to their oncogenic properties. Differential overexpression of CYP2J2 in tumors results in increased EET production. The role of EET in tumorigenesis is quite clear, but inhibition of CYP2J2 on EET formation with its molecular target is poorly understood. Research is ongoing to identify CYP2J2 inhibitors and the role of the CYP2J2\/EET axis in halting tumorigenesis. In these contexts, we aimed to address the same through in silico, in vitro, and in vivo approaches using crocetin, a phyto-based druggable molecule. In vitro mechanistic investigations using human liver microsomes (HLM) indicate that crocetin could act as a specific and reversible CYP2J2 inhibitor. In silico molecular docking analysis and molecular dynamics (MD) simulation explicate strong and stable interactions between crocetin and active site of human CYP2J2. In vivo investigations in BALB\/c mice reveal that crocetin could enhance the plasma exposure of rivaroxaban (CYP2J2 substrate) by delaying metabolism and attenuating CYP2J2 protein expression in the liver tissues. Additionally, in vitro studies using HLM and mouse liver microsomes (MLM) suggest that crocetin could substantially hinder EET formation. Thereafter, crocetin showcases its antitumor effect in the mouse model of breast cancer involving downregulation of CYP2J2 expression and impediment of EET formation in the tumor tissues. Further, proteomics data from crocetin-treated tumor tissues with gene ontology analysis (KEGG database) reflect upregulation\/downregulation of key proteins and biological processes associated with attenuating tumorigenesis. It is a footstep toward understanding the CYP2J2\/EET axis for targeted breast cancer therapy.<\/jats:p>","DOI":"10.1021\/acsomega.5c03187","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T01:02:07Z","timestamp":1786669327000},"page":"48778-48796","source":"Crossref","is-referenced-by-count":0,"title":["Crocetin Halts\nTumorigenesis in Metastatic Breast\nCancer via Disrupting CYP2J2\/EET Axis"],"prefix":"10.1021","volume":"11","author":[{"given":"Diksha","family":"Manhas","sequence":"first","affiliation":[{"name":"CSIR-Indian Institute of Integrative Medicine , , ,","place":["Jammu, India, 180001"]},{"name":"Academy of Scientific and Innovative Research (AcSIR) , ,","place":["Ghaziabad, India, 201002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashiya","family":"Jamwal","sequence":"additional","affiliation":[{"name":"CSIR-Indian Institute of Integrative Medicine , , ,","place":["Jammu, India, 180001"]},{"name":"Academy of 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180001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinay","family":"Kumar","sequence":"additional","affiliation":[{"name":"Jadavpur University , , ,","place":["Kolkata, India, 700032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4796-3915","authenticated-orcid":true,"given":"Probir Kumar","family":"Ojha","sequence":"additional","affiliation":[{"name":"Jadavpur University , , ,","place":["Kolkata, India, 700032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6224-3214","authenticated-orcid":true,"given":"Sanghapal D.","family":"Sawant","sequence":"additional","affiliation":[{"name":"Academy of Scientific and Innovative Research (AcSIR) , ,","place":["Ghaziabad, India, 201002"]},{"name":"CSIR-Indian Institute of Integrative Medicine , , ,","place":["Jammu, India, 180001"]},{"name":"CSIR-National Chemical Laboratory , , ,","place":["Pune, India, 411008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2811-482X","authenticated-orcid":true,"given":"Swarnendu","family":"Bag","sequence":"additional","affiliation":[{"name":"Academy of Scientific and Innovative Research (AcSIR) , ,","place":["Ghaziabad, India, 201002"]},{"name":"CSIR-Institute of Genomics & Integrative Biology , , ,","place":["New Delhi, India, 110025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8920-2383","authenticated-orcid":true,"given":"Anindya","family":"Goswami","sequence":"additional","affiliation":[{"name":"CSIR-Indian Institute of Integrative Medicine , , ,","place":["Jammu, India, 180001"]},{"name":"Academy of Scientific and Innovative Research (AcSIR) , ,","place":["Ghaziabad, India, 201002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7868-0240","authenticated-orcid":true,"given":"Utpal","family":"Nandi","sequence":"additional","affiliation":[{"name":"CSIR-Indian Institute of Integrative Medicine , , ,","place":["Jammu, India, 180001"]},{"name":"Academy of Scientific and Innovative Research (AcSIR) , ,","place":["Ghaziabad, India, 201002"]},{"name":"Bose Institute , Unified Academic Campus , ,","place":["Kolkata, India, 700091"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"issue":"3","key":"2026083119122117400_cit1","doi-asserted-by":"publisher","first-page":"94","DOI":"10.3390\/jox11030007","article-title":"The central role of cytochrome P450\nin xenobiotic metabolism\u2500a brief review on a fascinating enzyme\nfamily","volume":"11","author":"Esteves","year":"2021","journal-title":"Journal of 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implications","volume":"82","author":"Fanni","year":"2021","journal-title":"Drug Dev. Res."},{"issue":"2","key":"2026083119122117400_cit5","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1124\/jpet.106.109215","article-title":"Variability of CYP2J2\nexpression in human fetal tissues","volume":"319","author":"Gaedigk","year":"2006","journal-title":"Journal of\nPharmacology and Experimental Therapeutics"},{"key":"2026083119122117400_cit6","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2020.107601","article-title":"CYP2J2 molecular\nrecognition: a new axis for therapeutic\ndesign","volume":"215","author":"Das","year":"2020","journal-title":"Pharmacology & therapeutics"},{"key":"2026083119122117400_cit7","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1186824","article-title":"Characterization\nof 15 CYP2J2 variants identified in\nthe Chinese Han population on the metabolism of ebastine and terfenadine\nin vitro","volume":"14","author":"Zou","year":"2023","journal-title":"Front. Pharmacol."},{"key":"2026083119122117400_cit8","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1007\/s10555-011-9315-y","article-title":"EET signaling\nin cancer","volume":"30","author":"Panigrahy","year":"2011","journal-title":"Cancer and Metastasis Reviews"},{"issue":"1","key":"2026083119122117400_cit9","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1172\/JCI58128","article-title":"Epoxyeicosanoids\nstimulate multiorgan metastasis and tumor dormancy\nescape in mice","volume":"122","author":"Panigrahy","year":"2012","journal-title":"J. Clin. Invest."},{"issue":"1","key":"2026083119122117400_cit10","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s13046-018-0694-6","article-title":"14, 15-EET induces\nbreast cancer cell EMT and cisplatin resistance by up-regulating integrin\n\u03b1v\u03b23 and activating FAK\/PI3K\/AKT signaling","volume":"37","author":"Luo","year":"2018","journal-title":"J. Exp. Clin. 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Ther."},{"key":"2026083119122117400_cit17","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.phymed.2018.03.032","article-title":"The inhibitory\npotential of Broussochalcone A for the human cytochrome P450 2J2 isoform\nand its anti-cancer effects via FOXO3 activation","volume":"42","author":"Park","year":"2018","journal-title":"Phytomedicine: international journal of phytotherapy and phytopharmacology"},{"key":"2026083119122117400_cit18","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.phymed.2016.12.001","article-title":"Identification\nof acetylshikonin as the novel CYP2J2 inhibitor with anti-cancer activity\nin HepG2 cells","volume":"24","author":"Park","year":"2017","journal-title":"Phytomedicine"},{"issue":"3","key":"2026083119122117400_cit19","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural products as sources of new\ndrugs from 1981\nto 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"issue":"2","key":"2026083119122117400_cit20","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3390\/metabo2020303","article-title":"A historical\noverview of natural\nproducts in drug discovery","volume":"2","author":"Dias","year":"2012","journal-title":"Metabolites"},{"issue":"3","key":"2026083119122117400_cit21","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1080\/10408690490441433","article-title":"Crocetin from\nsaffron: an active component of an ancient spice","volume":"44","author":"Giaccio","year":"2004","journal-title":"Critical reviews in food science and nutrition"},{"issue":"1","key":"2026083119122117400_cit22","doi-asserted-by":"publisher","first-page":"173","DOI":"10.2174\/138920112798868566","article-title":"Crocetin: an agent derived from saffron for prevention and therapy\nfor cancer","volume":"13","author":"G Gutheil","year":"2012","journal-title":"Curr. Pharm. Biotechnol."},{"issue":"3","key":"2026083119122117400_cit23","doi-asserted-by":"publisher","DOI":"10.1177\/1010428317694536","article-title":"Crocetin shifts autophagic\ncell survival to death of breast cancer\ncells in chemotherapy","volume":"39","author":"Zhang","year":"2017","journal-title":"Tumor Biol."},{"issue":"02","key":"2026083119122117400_cit24","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1055\/s-0030-1250178","article-title":"Crocetin inhibits invasiveness of\nMDA-MB-231 breast\ncancer cells via downregulation of matrix metalloproteinases","volume":"77","author":"Chryssanthi","year":"2011","journal-title":"Planta medica"},{"issue":"8","key":"2026083119122117400_cit25","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1089\/dna.2018.4248","article-title":"A comparative\nstudy on anti-invasion, antimigration, and antiadhesion effects of\nthe bioactive carotenoids of saffron on 4T1 breast cancer cells through\ntheir effects on Wnt\/\u03b2-catenin pathway genes","volume":"37","author":"Arzi","year":"2018","journal-title":"DNA and cell biology"},{"key":"2026083119122117400_cit26","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1016\/j.ijbiomac.2020.04.063","article-title":"Saffron\ncarotenoids change the superoxide\ndismutase activity in breast cancer: In vitro, in vivo and in silico\nstudies","volume":"158","author":"Hashemi","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"issue":"13","key":"2026083119122117400_cit27","doi-asserted-by":"publisher","first-page":"3916","DOI":"10.1080\/07391102.2019.1668302","article-title":"Interaction\nof saffron carotenoids\nwith catalase: in vitro, in vivo and molecular docking studies","volume":"38","author":"Hashemi","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"issue":"1","key":"2026083119122117400_cit28","doi-asserted-by":"publisher","first-page":"94","DOI":"10.22074\/cellj.2016.3901","article-title":"Comparative study on\nthe preventive effect of saffron\ncarotenoids, crocin and crocetin, in NMU-induced breast cancer in\nrats","volume":"19","author":"Sajjadi","year":"2016","journal-title":"Cell J."},{"key":"2026083119122117400_cit29","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.745683","article-title":"Crocetin: a systematic review","volume":"12","author":"Guo","year":"2022","journal-title":"Frontiers in pharmacology"},{"key":"2026083119122117400_cit30","doi-asserted-by":"publisher","first-page":"21494","DOI":"10.1021\/acsomega.4c02116","article-title":"ADME\/PK Insights of Crocetin: A Molecule\nHaving an Unusual Chemical\nStructure with Druglike Features","volume":"9","author":"Manhas","year":"2024","journal-title":"ACS Omega"},{"issue":"3","key":"2026083119122117400_cit31","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.dmpk.2018.02.001","article-title":"Terfenadone is a strong inhibitor\nof CYP2J2 present in the human liver and intestinal microsomes","volume":"33","author":"Lee","year":"2018","journal-title":"Drug metabolism and pharmacokinetics"},{"key":"2026083119122117400_cit32","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1007\/BF03253143","article-title":"Potential of hydroxyebastine\nand terfenadine alcohol\nto inhibit the human cytochrome P450 2J2 isoform","volume":"54","author":"Yoon","year":"2011","journal-title":"Journal of the Korean Society for Applied Biological Chemistry"},{"key":"2026083119122117400_cit33","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.phymed.2017.12.026","article-title":"Plant natural product plumbagin presents potent inhibitory\neffect on human cytochrome P450 2J2 enzyme","volume":"39","author":"Lu","year":"2018","journal-title":"Phytomedicine: international journal of phytotherapy and phytopharmacology"},{"issue":"5","key":"2026083119122117400_cit34","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1124\/dmd.111.043505","article-title":"Identifying\na selective substrate and inhibitor pair for the evaluation of CYP2J2\nactivity","volume":"40","author":"Lee","year":"2012","journal-title":"Drug Metab. 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Lett."},{"key":"2026083119122117400_cit38","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.856784","article-title":"Potent inhibition\nof human cytochrome P450 3A4 by biflavone components from Ginkgo biloba\nand Selaginella tamariscina","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"2026083119122117400_cit39","doi-asserted-by":"crossref","unstructured":"Wadanambi, P.; Mannapperuma, U.; Jayathilaka, N.\n          Molecular docking\nand ADMET based study to identify potential phytochemical inhibitors\nfor papain-like protease of SARS-CoV-2.  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Pharmacol."},{"issue":"7","key":"2026083119122117400_cit41","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1016\/j.tiv.2015.06.014","article-title":"Inhibition of human\ncytochrome P450 enzymes by licochalcone A, a naturally occurring constituent\nof licorice","volume":"29","author":"He","year":"2015","journal-title":"Toxicology in vitro"},{"issue":"3","key":"2026083119122117400_cit42","doi-asserted-by":"publisher","first-page":"311","DOI":"10.3109\/03602532.2013.806537","article-title":"Cytochrome P450 2J2:\ndistribution, function, regulation, genetic polymorphisms and clinical\nsignificance","volume":"45","author":"Xu","year":"2013","journal-title":"Drug metabolism reviews"},{"key":"2026083119122117400_cit43","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s10557-020-07129-z","article-title":"Identifying the dominant contribution of human cytochrome P450 2J2\nto the metabolism of rivaroxaban, an oral anticoagulant","volume":"36","author":"Zhao","year":"2022","journal-title":"Cardiovasc. Drugs Ther."},{"key":"2026083119122117400_cit44","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.914842","article-title":"Risk assessment\nand molecular mechanism study of drug-drug interactions between rivaroxaban\nand tyrosine kinase inhibitors mediated by CYP2J2\/3A4 and BCRP\/P-gp","volume":"13","author":"Zhao","year":"2022","journal-title":"Front. Pharmacol."},{"issue":"10","key":"2026083119122117400_cit45","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1124\/dmd.122.000928","article-title":"Inhibition of\ncytochrome P450 2J2-mediated metabolism\nof rivaroxaban and arachidonic acid by ibrutinib and osimertinib","volume":"50","author":"Wang","year":"2022","journal-title":"Drug Metab. Dispos."},{"issue":"7","key":"2026083119122117400_cit46","doi-asserted-by":"publisher","first-page":"3460","DOI":"10.1074\/jbc.271.7.3460","article-title":"Molecular\nCloning and Expression of CYP2J2, a Human Cytochrome P450 Arachidonic\nAcid Epoxygenase Highly Expressed in Heart (\u2217)","volume":"271","author":"Wu","year":"1996","journal-title":"J. Biol. Chem."},{"issue":"1","key":"2026083119122117400_cit47","doi-asserted-by":"publisher","first-page":"20.2.1","DOI":"10.1002\/0471142735.im2002s39","article-title":"Mouse 4T1\nbreast tumor model","volume":"39","author":"Pulaski","year":"2000","journal-title":"Curr. Protoc. 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