{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:53:08Z","timestamp":1781484788263,"version":"3.54.1"},"reference-count":36,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Yi He","award":["2025AC014"],"award-info":[{"award-number":["2025AC014"]}]},{"name":"Yi He","award":["LMS25H050003"],"award-info":[{"award-number":["LMS25H050003"]}]},{"name":"Daoyun Zhang","award":["2023C03057"],"award-info":[{"award-number":["2023C03057"]}]},{"name":"Daoyun Zhang","award":["2024-YB-075]"],"award-info":[{"award-number":["2024-YB-075]"]}]},{"name":"Daoyun Zhang","award":["2025BS009"],"award-info":[{"award-number":["2025BS009"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Technol Cancer Res Treat"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Cystoscopy-based diagnosis and surveillance of bladder cancer (BC) remain challenging. This study presents a urine-based assay that enriches DNA-methylation signals via PCR enrichment and applies a machine-learning model to enable cost-effective early detection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a prospective cohort at hospital (May 2022-November 2023), 155 individuals were enrolled, BC was diagnosed and confirmed by cystoscopy-guided biopsy and histopathology. Targeted next-generation sequencing of urine DNA quantified methylation at 44 CpG sites within IRF4, PENK and PXDN. Supervised classifiers trained on these features distinguished tumor from non-tumor urine samples. Systems analyses around IRF4\/PENK\/PXDN mapped signaling pathways, protein interaction modules and tumor-microenvironment contexts in BC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Using 155 urine samples (68 BC, 87 non-BC) with methylation and transcript expression data in TCGA-BLCA, we found significantly increased methylation of IRF4, PENK, and PXDN in BC (P &lt; 0.0001). Corresponding mRNA levels of IRF4 and PENK were significantly downregulated in tumor tissues, with PXDN showing a declining trend. Methylation of IRF4 and PXDN negatively correlated with their expression (P &lt; 0.0001). A 41-CpG-site random forest classifier targeting IRF4, PENK, and PXND (BladderCando model) demonstrated excellent performance in distinguishing BC from non-BC individuals (AUC = 0.9783, F1 = 0.9773), outperforming urine cytology for low-grade BC detection. Co-expression and enrichment analyses identified DCN as a central hub gene, primarily linked to ECM functions. High expression of PXDN, IRF4, and DCN correlated with upregulated immune checkpoint genes and increased immune cell infiltration. Single-cell sequencing revealed PXDN in fibroblasts and endothelial cells, DCN in fibroblasts, and IRF4 in T cells, with expression patterns in urine mirroring tumor tissue profiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study establishes IRF4, PENK and PXDN methylation in urine as robust molecular signatures for BC detection, with machine-learning integration markedly enhancing diagnostic precision. Beyond early surveillance, these epigenetic alterations delineate tumor-microenvironment interactions that may inform future therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/15330338261453486","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:37:37Z","timestamp":1781224657000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Urine IRF4\/PENK\/PXDN Methylation Signatures Enable Machine Learning-Driven Bladder Cancer Detection and Microenvironment Dissection"],"prefix":"10.1177","volume":"25","author":[{"given":"Yi","family":"He","sequence":"first","affiliation":[{"name":"The Affiliated Hospital of Jiaxing University"},{"name":"Jiaxing University Master Degree Cultivation Base"},{"name":"Zhejiang Chinese Medical University"},{"name":"The First Hospital of 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