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Because epigenetic reprogramming and metabolic rewiring jointly shape BLCA biology, we sought to identify epigenomically informed biomarkers with functional relevance.\n                    <jats:bold>Methods:<\/jats:bold>\n                    Epigenome (genome-wide promoter DNA methylation) and matched transcriptome (RNA sequencing) profiles from tumor and adjacent normal samples were integrated to identify genes with concordant differential methylation and expression patterns. A survival-oriented machine learning framework distilled these candidates into a 25-gene signature. The prognostic performance was evaluated in 4 independent BLCA cohorts. Multilayer characterization included the computational inference of tumor-infiltrating immune cells and\n                    <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                    drug sensitivity prediction. The functional relevance of key lipid metabolic hub genes was confirmed by pharmacological inhibition in BLCA cell line models, followed by colony formation and migration assays.\n                    <jats:bold>Results:<\/jats:bold>\n                    The signature, enriched for cell cycle regulation and lipid metabolism, stratified patients into high- and low-risk groups across the discovery and 4 validation datasets. The prognostic value remained independent of age, pathological stage, and common genomic alterations. Low-risk tumors exhibited computationally inferred immune-inflamed phenotypes, whereas high-risk tumors exhibited lower immune engagement and lower half-maximal inhibitory concentration values for several drugs. Network analysis identified fatty acid synthase and stearoyl-coenzyme A desaturase as central nodes; their inhibition reduced BLCA cell proliferation and migration, supporting pathway-level functional relevance.\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    By integrating epigenomic and transcriptomic layers with machine learning, we delineated a lipid-centric 25-gene signature that delivers stage-independent prognostication, illuminates tumor\u2013immune interactions, and nominates actionable therapeutic targets. This experimentally vetted multi-omics framework advances precision oncology for BLCA.\n                  <\/jats:p>","DOI":"10.34133\/csbj.0139","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T21:31:36Z","timestamp":1780435896000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["Epigenomics-Guided Multi-Omics Integration Uncovers a Lipid-Metabolic Signature with Translational Utility in Bladder Cancer"],"prefix":"10.34133","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0339-5226","authenticated-orcid":false,"given":"Yu-De","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Urology, \rChina Medical University Hospital, Taichung, Taiwan."},{"name":"Graduate Institute of Biomedical Sciences, \rChina Medical University, Taichung, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yo-Liang","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, \rChina Medical University Hospital, Taichung, Taiwan."},{"name":"School of Medicine, \rChina Medical University, Taichung, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2880-8365","authenticated-orcid":false,"given":"Chia-Hsin","family":"Liu","sequence":"additional","affiliation":[{"name":"Cancer Biology and Precision Therapeutics Center, \rChina Medical University, Taichung, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ting","family":"Su","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, \rChina Medical University, Taichung, Taiwan."},{"name":"Department of Obstetrics and Gynecology, Department of Medical Research, \rChina Medical University Hospital, Taichung, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0733-5706","authenticated-orcid":false,"given":"Pei-Chun","family":"Shen","sequence":"additional","affiliation":[{"name":"Cancer Biology and Precision Therapeutics Center, \rChina Medical University, Taichung, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1671-4863","authenticated-orcid":false,"given":"Fang-Hsin","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Nuclear Engineering and Science, \rNational Tsing Hua University, Hsinchu, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5689-9850","authenticated-orcid":false,"given":"Chia-Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, \rKaohsiung Medical University, Kaohsiung, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9691-7507","authenticated-orcid":false,"given":"Shu-Chi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, \rKaohsiung Medical University, Kaohsiung, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7116-4304","authenticated-orcid":false,"given":"Wen-Lung","family":"Ma","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, \rChina Medical University, Taichung, Taiwan."},{"name":"Department of Medical Research, Organ Transplantation Center, \rChina Medical University Hospital, Taichung, Taiwan."},{"name":"Ph.D. Program for Health Science and Industry, Center of Tumor Biology, School of Medicine, \rChina Medical University, Taichung, Taiwan."},{"name":"Office of Research and Development, \rAsia University, Taichung, 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