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We conducted an exploratory investigation within this framework to understand the molecular basis of lymphovascular invasion (LVI), a critical determinant of metastatic potential in clear cell renal cell carcinoma (ccRCC). We analyzed 31 ccRCC specimens (11 LVI+, 20 LVI\u2212) from the National Cancer Center Hospital East using whole\u2010genome sequencing, RNA sequencing, and proteomic profiling. Our findings were integrated with public single\u2010cell RNA sequencing (GSE159115) and spatial transcriptomics (GSE175540) datasets to provide a broader biological context. LVI+ tumors consistently showed a distinctive hepatic\u2010lineage gene expression signature, with significant upregulation of aldolase B (ALDOB) and other liver\u2010specific metabolism genes at both the RNA and protein levels. Single\u2010cell analysis identified a previously unrecognized hepatic\u2010differentiated tumor subpopulation expressing master transcription factors HNF1A and HNF4A, which was positioned at the terminal stages of tumor evolution. Comparison with established hepatocyte gene signatures from three independent databases confirmed enrichment of hepatic metabolic programs in this subpopulation. Spatial transcriptomics revealed preferential localization within hypoxic tumor regions. A metabolic program resembling hepatic lineage differentiation, associated with aggressive disease features including LVI and hypoxic microenvironments, offers preliminary insights into renal cancer progression and potential biomarker development. This is a discovery\u2010based, hypothesis\u2010generating study; all findings require independent functional validation before clinical application.<\/jats:p>","DOI":"10.1002\/cam4.71843","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T04:14:27Z","timestamp":1776226467000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatic\u2010Differentiated Subpopulation in Clear Cell Renal Cell Carcinoma: A Multi\u2010Omics Analysis of Tumors With Lymphovascular Invasion"],"prefix":"10.1002","volume":"15","author":[{"given":"Shugo","family":"Yajima","sequence":"first","affiliation":[{"name":"Department of Urology National Cancer Center Hospital East  Kashiwa 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