{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:02:57Z","timestamp":1789344177990,"version":"build-2803163510"},"reference-count":31,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M732157"],"award-info":[{"award-number":["2023M732157"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81902513"],"award-info":[{"award-number":["81902513"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82100680"],"award-info":[{"award-number":["82100680"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82102093"],"award-info":[{"award-number":["82102093"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019447","name":"Applied Basic Research Project of Shanxi Province, China","doi-asserted-by":"publisher","award":["202303021211114"],"award-info":[{"award-number":["202303021211114"]}],"id":[{"id":"10.13039\/501100019447","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Epoxide hydrolase 2 (EPHX2) is a key enzyme in fatty acid metabolism that metabolizes epoxyeicosatrienoic acids (EETs), lipid mediators involved in inflammation, angiogenesis, and carcinogenesis. However, the role and mechanism of EPHX2 in colorectal cancer (CRC) migration remain unclear. In this study, we employed an integrated approach of bioinformatics and functional experiments to examine EPHX2 expression, its clinical implications, and its mechanistic role in CRC migration. Our results showed that EPHX2 was significantly downregulated in CRC tissues, and its low expression correlated with poor prognosis. Overexpression of EPHX2 led to accumulation of HDHA, HEPE, and HETE in CRC cells, whereas loss of EPHX2 increased CXCL levels and suppressed mitochondrial biogenesis via EET accumulation. Furthermore, loss of EPHX2 promoted cell migration through ROS and CXCL signaling. Collectively, loss of EPHX2 accelerates cell migration via EET accumulation\u2010dependent chemokine elevation and mitochondrial biogenesis impairment in CRC. These findings reveal a novel metabolic\u2010mitochondrial axis in CRC progression and highlight EPHX2 as a potential therapeutic target.<\/jats:p>","DOI":"10.1111\/cas.70537","type":"journal-article","created":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:10:56Z","timestamp":1789341056000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>EPHX2<\/scp>\n                    Loss Promotes\n                    <scp>CRC<\/scp>\n                    Migration via\n                    <scp>EET<\/scp>\n                    \u2010Dependent Chemokine Elevation and Mitochondrial Defect"],"prefix":"10.1111","author":[{"given":"Jianjun","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Medical Cellular Biology and Genetics, School of Basic Medical Science Shanxi Medical University; First Hospital of Shanxi Medical University  Taiyuan Shanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjia","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Medical Cellular Biology and Genetics, School of Basic Medical Science Shanxi Medical University  Taiyuan Shanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Cellular Biology and Genetics, School of Basic Medical Science Shanxi Medical University  Taiyuan Shanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology Roswell Park Comprehensive Cancer Center  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery Xijing Hospital, Air Force Military Medical University  Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Basic Medical Science Shanxi Medical University  Taiyuan Shanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Cellular Biology and Genetics, School of Basic Medical Science Shanxi Medical University  Taiyuan Shanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Tao","sequence":"additional","affiliation":[{"name":"Institutte of Basic Medicine and Forensic Medicine North Sichuan Medical College  Nanchong Sichuan China"},{"name":"Department of Pathology Affiliated Hospital of North Sichuan Medical College  Nanchong Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Cellular Biology and Genetics, School of Basic Medical Science Shanxi Medical University  Taiyuan Shanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yintao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Respiratory Oncology Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9785-6056","authenticated-orcid":false,"given":"Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Cellular Biology and Genetics, School of Basic Medical Science Shanxi Medical University  Taiyuan Shanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"issue":"3","key":"e_1_2_13_2_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray F.","year":"2024","journal-title":"CA: A Cancer Journal for Clinicians"},{"key":"e_1_2_13_3_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.semcdb.2019.05.018","article-title":"Metabolic Pathways Regulating Colorectal Cancer Initiation and Progression","volume":"98","author":"La Vecchia S.","year":"2020","journal-title":"Seminars in Cell & Developmental Biology"},{"issue":"1","key":"e_1_2_13_4_1","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41392-025-02311-x","article-title":"Mitochondrial Metabolism and Cancer Therapeutic Innovation","volume":"10","author":"Du H.","year":"2025","journal-title":"Signal Transduction and Targeted Therapy"},{"issue":"2","key":"e_1_2_13_5_1","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.ajpath.2010.10.002","article-title":"Arachidonic Acid Pathway Members PLA2G7, HPGD, EPHX2, and CYP4F8 Identified as Putative Novel Therapeutic Targets in Prostate Cancer","volume":"178","author":"Vainio P.","year":"2011","journal-title":"American Journal of Pathology"},{"issue":"3","key":"e_1_2_13_6_1","doi-asserted-by":"crossref","DOI":"10.1002\/cnr2.70188","article-title":"A Comprehensive Analysis of Epoxide Hydrolase 2 (EPHX2) in Pan\u2010Cancer","volume":"8","author":"Hu W.","year":"2025","journal-title":"Cancer Reports (Hoboken)"},{"key":"e_1_2_13_7_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.pharmthera.2022.108213","article-title":"Crosstalk Between Adenosine Receptors and CYP450\u2010Derived Oxylipins in the Modulation of Cardiovascular, Including Coronary Reactive Hyperemic Response","volume":"240","author":"Nayeem M. A.","year":"2022","journal-title":"Pharmacology & Therapeutics"},{"issue":"3","key":"e_1_2_13_8_1","doi-asserted-by":"crossref","first-page":"650","DOI":"10.3892\/mmr.2021.12289","article-title":"Identification and Validation of EPHX2 as a Prognostic Biomarker in Hepatocellular Carcinoma","volume":"24","author":"Zhan K.","year":"2021","journal-title":"Molecular Medicine Reports"},{"key":"e_1_2_13_9_1","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2022.870721","article-title":"EPHX2 Inhibits Colon Cancer Progression by Promoting Fatty Acid Degradation","volume":"12","author":"Zhou Y.","year":"2022","journal-title":"Frontiers in Oncology"},{"key":"e_1_2_13_10_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbrep.2024.101912","article-title":"The Prognostic Significance of Epoxide Hydrolases in Colorectal Cancer","volume":"41","author":"Cao L.","year":"2025","journal-title":"Biochemistry and Biophysics Reports"},{"key":"e_1_2_13_11_1","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2025.1541429","article-title":"EPHX2 Overexpression Deters the Advancement of Clear Cell Renal Cell Carcinoma via Lipid Metabolism Reprogramming","volume":"15","author":"Guan B.","year":"2025","journal-title":"Frontiers in Oncology"},{"key":"e_1_2_13_12_1","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202507695","article-title":"CYP4X1\/sEH\u2010Dependent Endocannabinoid Metabolism Drives Fibroblast\u2010Mediated Immunosuppression to Limit Immunotherapy in Colon Cancer","volume":"13","author":"Mo M.","year":"2025","journal-title":"Advanced Science"},{"key":"e_1_2_13_13_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.prostaglandins.2020.106454","article-title":"Therapeutic Approaches to Diabetic Cardiomyopathy: Targeting the Antioxidant Pathway","volume":"150","author":"Arad M.","year":"2020","journal-title":"Prostaglandins & Other Lipid Mediators"},{"issue":"11","key":"e_1_2_13_14_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0294236","article-title":"SRplot: A Free Online Platform for Data Visualization and Graphing","volume":"18","author":"Tang D.","year":"2023","journal-title":"PLoS One"},{"issue":"42","key":"e_1_2_13_15_1","doi-asserted-by":"crossref","first-page":"5897","DOI":"10.1038\/onc.2017.167","article-title":"MCU\u2010Dependent Mitochondrial Ca2+ Inhibits NAD+\/SIRT3\/SOD2 Pathway to Promote ROS Production and Metastasis of HCC Cells","volume":"36","author":"Ren T.","year":"2017","journal-title":"Oncogene"},{"issue":"6","key":"e_1_2_13_16_1","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1016\/j.biocel.2012.03.006","article-title":"Standardized Mitochondrial Analysis Gives New Insights Into Mitochondrial Dynamics and OPA1 Function","volume":"44","author":"Chevrollier A.","year":"2012","journal-title":"International Journal of Biochemistry & Cell Biology"},{"key":"e_1_2_13_17_1","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.isci.2018.12.036","article-title":"Mitochondrial Populations Exhibit Differential Dynamic Responses to Increased Energy Demand During Exocytosis In\u00a0Vivo","volume":"11","author":"Porat\u2010Shliom N.","year":"2019","journal-title":"iScience"},{"issue":"1","key":"e_1_2_13_18_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.4103\/aja.aja_34_20","article-title":"Clinical Significance of EPHX2 Deregulation in Prostate Cancer","volume":"23","author":"Liu M. S.","year":"2021","journal-title":"Asian Journal of Andrology"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00405\u2010025\u201009762\u20106"},{"key":"e_1_2_13_20_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.biopha.2019.109274","article-title":"Mining Featured Biomarkers Associated With Vascular Invasion in HCC by Bioinformatics Analysis With TCGA RNA Sequencing Data","volume":"118","author":"Zhang R.","year":"2019","journal-title":"Biomedicine & Pharmacotherapy"},{"issue":"15","key":"e_1_2_13_21_1","doi-asserted-by":"crossref","first-page":"8024","DOI":"10.3390\/ijms25158024","article-title":"Upregulated Nuclear Expression of Soluble Epoxide Hydrolase Predicts Poor Outcome in Breast Cancer Patients: Importance of the Digital Pathology Approach","volume":"25","author":"Montecillo\u2010Aguado M.","year":"2024","journal-title":"International Journal of Molecular Sciences"},{"issue":"15","key":"e_1_2_13_22_1","doi-asserted-by":"crossref","first-page":"8745","DOI":"10.3390\/ijms23158745","article-title":"Norepinephrine Inhibits Lipopolysaccharide\u2010Stimulated TNF\u2010\u03b1 but Not Oxylipin Induction in n\u20103\/n\u20106 PUFA\u2010Enriched Cultures of Circumventricular Organs","volume":"23","author":"Pflieger F. J.","year":"2022","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_13_23_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.bioorg.2024.107579","article-title":"Inhibition of the STAT3\u2010EPHX2 Axis Promotes Regression of Ulcerative Colitis by Treatment With Novel Porphyrin Derivative","volume":"150","author":"Xu B.","year":"2024","journal-title":"Bioorganic Chemistry"},{"issue":"1","key":"e_1_2_13_24_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13024-025-00844-x","article-title":"Inhibition of Soluble Epoxide Hydrolase Confers Neuroprotection and Restores Microglial Homeostasis in a Tauopathy Mouse Model","volume":"20","author":"Wang S.","year":"2025","journal-title":"Molecular Neurodegeneration"},{"issue":"8036","key":"e_1_2_13_25_1","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1038\/s41586-024-08022-7","article-title":"Gasdermin D\u2010Mediated Metabolic Crosstalk Promotes Tissue Repair","volume":"634","author":"Chi Z.","year":"2024","journal-title":"Nature"},{"issue":"22","key":"e_1_2_13_26_1","doi-asserted-by":"crossref","DOI":"10.1172\/JCI129679","article-title":"sEH Promotes Macrophage Phagocytosis and Lung Clearance of \n                     Streptococcus pneumoniae","volume":"131","author":"Li H.","year":"2021","journal-title":"Journal of Clinical Investigation"},{"issue":"4","key":"e_1_2_13_27_1","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1002\/bab.2586","article-title":"Characterization and Validation of Fatty Acid Metabolism\u2010Related Genes Predicting Prognosis, Immune Infiltration, and Drug Sensitivity in Endometrial Cancer","volume":"71","author":"Li H.","year":"2024","journal-title":"Biotechnology and Applied Biochemistry"},{"issue":"11","key":"e_1_2_13_28_1","doi-asserted-by":"crossref","first-page":"21260","DOI":"10.1002\/jcp.28731","article-title":"Identification of EPHX2 and RMI2 as Two Novel Key Genes in Cervical Squamous Cell Carcinoma by an Integrated Bioinformatic Analysis","volume":"234","author":"Liu J.","year":"2019","journal-title":"Journal of Cellular Physiology"},{"issue":"1","key":"e_1_2_13_29_1","doi-asserted-by":"crossref","first-page":"36772","DOI":"10.1038\/s41598-025-20762-8","article-title":"Bioinformatics Analyses of Comorbid Mechanisms Between Psoriasis and Type 2 Diabetes Mellitus","volume":"15","author":"Wang Z.","year":"2025","journal-title":"Scientific Reports"},{"issue":"1","key":"e_1_2_13_30_1","doi-asserted-by":"crossref","first-page":"16504","DOI":"10.1038\/s41598-020-73700-1","article-title":"Transcriptome\u2010Wide Analysis and Modelling of Prognostic Alternative Splicing Signatures in Invasive Breast Cancer: A Prospective Clinical Study","volume":"10","author":"Wang L.","year":"2020","journal-title":"Scientific Reports"},{"issue":"10","key":"e_1_2_13_31_1","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.3390\/biom12101401","article-title":"Label\u2010Free Quantitative Proteomics Analysis of Adriamycin Selected Multidrug Resistant Human Lung Cancer Cells","volume":"12","author":"Efeoglu E.","year":"2022","journal-title":"Biomolecules"},{"key":"e_1_2_13_32_1","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2021.647253","article-title":"Integrative Analysis of Methylation and Copy Number Variations of Prostate Adenocarcinoma Based on Weighted Gene co\u2010Expression Network Analysis","volume":"11","author":"Hou Y.","year":"2021","journal-title":"Frontiers in Oncology"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70537","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cas.70537","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70537","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:11:00Z","timestamp":1789341060000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.70537"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,13]]},"references-count":31,"alternative-id":["10.1111\/cas.70537"],"URL":"https:\/\/doi.org\/10.1111\/cas.70537","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,13]]},"assertion":[{"value":"2026-01-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cas.70537"}}