{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T02:54:19Z","timestamp":1771815259491,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T00:00:00Z","timestamp":1748217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82303866"],"award-info":[{"award-number":["82303866"]}],"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":["GZC20230961"],"award-info":[{"award-number":["GZC20230961"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"Postdoctoral Fellowship Program of China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["82303866"],"award-info":[{"award-number":["82303866"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"Postdoctoral Fellowship Program of China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["GZC20230961"],"award-info":[{"award-number":["GZC20230961"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, necessitating the identification of novel biomarkers for improved prognosis and diagnosis. This study investigates the role of epoxide hydrolase 4 (EPHX4), a member of the epoxide hydrolase family, in LUAD. Using data sourced from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, which were subsequently validated by the Gene Expression Omnibus (GEO), we analyzed levels of EPHX4 expression, mutation, and methylation in tumors versus normal tissues. Our findings revealed a significant upregulation of EPHX4 in LUAD tissues compared to normal lung tissues (p &lt; 0.001), correlating with poorer overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). Furthermore, EPHX4 exhibited considerable diagnostic potential, as demonstrated by an area under the curve (AUC) of 0.854 in a Receiver Operating Characteristic (ROC) analysis. Notably, EPHX4 expression was associated with immune infiltration, specifically Th2 cells, neutrophils, and macrophages, along with immune checkpoint molecules including PD-L1, PD-L2, and TIM-3. Additionally, EPHX4 was involved in pivotal tumor-associated pathways, particularly cell cycle regulation. In conclusion, an elevated EPHX4 expression is indicative of poorer prognosis in LUAD and may play a role in immune evasion and cell cycle dysregulation, highlighting its potential as a promising biomarker for the diagnosis and prognostic prediction of LUAD.<\/jats:p>","DOI":"10.3390\/ijms26115095","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T11:12:57Z","timestamp":1748344377000},"page":"5095","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrative Analysis of EPHX4 as a Novel Prognostic and Diagnostic Biomarker in Lung Adenocarcinoma"],"prefix":"10.3390","volume":"26","author":[{"given":"Pengze","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathology, School of Medicine, Jinan University, Guangzhou 510632, China"},{"name":"School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Jinan University, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/S0140-6736(22)01694-4","article-title":"Lung Cancer Screening","volume":"401","author":"Adams","year":"2023","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1002\/1878-0261.13554","article-title":"FBXL16 Promotes Cell Growth and Drug Resistance in Lung Adenocarcinomas with KRAS Mutation by Stabilizing IRS1 and Upregulating IRS1\/AKT Signaling","volume":"18","author":"Morel","year":"2024","journal-title":"Mol. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4413","DOI":"10.1038\/s41388-021-01853-y","article-title":"A Risk Model Developed Based on Tumor Microenvironment Predicts Overall Survival and Associates with Tumor Immunity of Patients with Lung Adenocarcinoma","volume":"40","author":"Wu","year":"2021","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"996","DOI":"10.3348\/kjr.2015.16.5.996","article-title":"Breast Microcalcifications: Diagnostic Outcomes According to Image-Guided Biopsy Method","volume":"16","author":"Bae","year":"2015","journal-title":"Korean J. Radiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ccell.2020.06.001","article-title":"Oxidative Stress in Cancer","volume":"38","author":"Hayes","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0009-2797(00)00197-6","article-title":"Epoxide Hydrolases: Biochemistry and Molecular Biology","volume":"129","author":"Fretland","year":"2000","journal-title":"Chem. Biol. Interact."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Morisseau, C., Kodani, S.D., Kamita, S.G., Yang, J., Lee, K.S.S., and Hammock, B.D. (2021). Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094993"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.biochi.2019.01.020","article-title":"Role of Epoxy-Fatty Acids and Epoxide Hydrolases in the Pathology of Neuro-Inflammation","volume":"159","author":"Kodani","year":"2019","journal-title":"Biochimie"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gautheron, J., and J\u00e9ru, I. (2020). The Multifaceted Role of Epoxide Hydrolases in Human Health and Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010013"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1194\/jlr.M024448","article-title":"EH3 (ABHD9): The First Member of a New Epoxide Hydrolase Family with High Activity for Fatty Acid Epoxides","volume":"53","author":"Decker","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Cao, L., Ba, Y., Chen, F., Li, D., Zhang, S., and Zhang, H. (2025). The Prognostic Significance of Epoxide Hydrolases in Colorectal Cancer. Biochem. Biophys. Rep., 41.","DOI":"10.1016\/j.bbrep.2024.101912"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101411","DOI":"10.1016\/j.bjorl.2024.101411","article-title":"Comprehensive Analysis of the Immune Implication of EPHX4 Gene in Laryngeal Squamous Cell Carcinoma","volume":"90","author":"Shen","year":"2024","journal-title":"Braz. J. Otorhinolaryngol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s00018-024-05183-6","article-title":"PALB2-Mutated Human Mammary Cells Display a Broad Spectrum of Morphological and Functional Abnormalities Induced by Increased TGF\u03b2 Signaling","volume":"81","author":"Tuppurainen","year":"2024","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1023\/A:1005402020569","article-title":"The Human Nuclear-Encoded Acyl Carrier Subunit (NDUFAB1) of the Mitochondrial Complex I in Human Pathology","volume":"22","author":"Triepels","year":"1999","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1042\/BJ20081973","article-title":"TVP23 Interacts Genetically with the Yeast SNARE VTI1 and Functions in Retrograde Transport from the Early Endosome to the Late Golgi","volume":"419","author":"Stein","year":"2009","journal-title":"Biochem. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1016\/j.jtho.2022.09.109","article-title":"Predictive Biomarkers for Immunotherapy in Lung Cancer: Perspective From the International Association for the Study of Lung Cancer Pathology Committee","volume":"17","author":"Schalper","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e542","DOI":"10.1016\/S1470-2045(16)30406-5","article-title":"Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy","volume":"17","author":"Gibney","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/s41568-024-00743-1","article-title":"Macrophages and T Cells in Metabolic Disorder-Associated Cancers","volume":"24","author":"Taranto","year":"2024","journal-title":"Nat. Rev. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"217466","DOI":"10.1016\/j.canlet.2025.217466","article-title":"Metabolic Reprogramming of Neutrophils in the Tumor Microenvironment: Emerging Therapeutic Targets","volume":"612","author":"Huang","year":"2025","journal-title":"Cancer Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1136\/gutjnl-2024-333617","article-title":"CAF-Macrophage Crosstalk in Tumour Microenvironments Governs the Response to Immune Checkpoint Blockade in Gastric Cancer Peritoneal Metastases","volume":"74","author":"Li","year":"2025","journal-title":"Gut"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"112102","DOI":"10.1016\/j.intimp.2024.112102","article-title":"Targeting SIGLEC15 as an Emerging Immunotherapy for Anaplastic Thyroid Cancer","volume":"133","author":"Bao","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s43018-024-00893-z","article-title":"Resistance Mechanisms and Therapeutic Strategies of CDK4 and CDK6 Kinase Targeting in Cancer","volume":"6","author":"Asciolla","year":"2025","journal-title":"Nat. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1158\/2159-8290.CD-19-0528","article-title":"Transcription-Associated Cyclin-Dependent Kinases as Targets and Biomarkers for Cancer Therapy","volume":"10","author":"Chou","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/s41523-022-00494-y","article-title":"Crystal Structure of Active CDK4-Cyclin D and Mechanistic Basis for Abemaciclib Efficacy","volume":"8","author":"Gharbi","year":"2022","journal-title":"npj Breast Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6224","DOI":"10.7150\/thno.36281","article-title":"A Nano-Liposome Formulation of the PARP Inhibitor Talazoparib Enhances Treatment Efficacy and Modulates Immune Cell Populations in Mammary Tumors of BRCA-Deficient Mice","volume":"9","author":"Zhang","year":"2019","journal-title":"Theranostics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3357","DOI":"10.1038\/s41418-021-00823-x","article-title":"Ki-67 Gene Expression","volume":"28","author":"Uxa","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Teli, G., Maji, L., Pal, R., Maheshwari, N., Purawarga Matada, G.S., Chawla, P.A., and Chawla, V. (2025). Recent Advancements in Mechanistic Research, Therapeutic Potential, and Structure-Activity Relationships of Aurora Kinase Inhibitors in Cancer Therapies. Bioorganic Chem., 154.","DOI":"10.1016\/j.bioorg.2024.107976"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1002\/path.2440","article-title":"The Human Protein Atlas\u2014A Tool for Pathology","volume":"216","author":"Uhlen","year":"2008","journal-title":"J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal Dynamics of Intratumoral Immune Cells Reveal the Immune Landscape in Human Cancer","volume":"39","author":"Bindea","year":"2013","journal-title":"Immunity"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"H\u00e4nzelmann, S., Castelo, R., and Guinney, J. (2013). GSVA: Gene Set Variation Analysis for Microarray and RNA-Seq Data. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-7"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for Analysis of Tumor-Infiltrating Immune Cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.neo.2022.01.001","article-title":"UALCAN: An Update to the Integrated Cancer Data Analysis Platform","volume":"25","author":"Chandrashekar","year":"2022","journal-title":"Neoplasia"},{"key":"ref_35","first-page":"100141","article-title":"clusterProfiler 4.0: A Universal Enrichment Tool for Interpreting Omics Data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"D730","DOI":"10.1093\/nar\/gkae1113","article-title":"The STRING Database in 2025: Protein Networks with Directionality of Regulation","volume":"53","author":"Szklarczyk","year":"2025","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/11\/5095\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:40:26Z","timestamp":1760031626000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/11\/5095"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,26]]},"references-count":36,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26115095"],"URL":"https:\/\/doi.org\/10.3390\/ijms26115095","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,26]]}}}