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The targeting of senescent cells has recently emerged as a promising therapeutic strategy. Nevertheless, the precise role of cellular senescence in the pathophysiology of ccRCC has yet to be comprehensively elucidated. This study sought to investigate the role of cellular senescence levels in ccRCC through comprehensive transcriptomic, proteomic, spatial transcriptomic, and single\u2010cell analyses. The study determined that elevated levels of cellular senescence contribute to a suppressed immune microenvironment, thereby exacerbating the prognosis for ccRCC patients. We utilized an extensive array of machine learning algorithms, in conjunction with multi\u2010omics technologies, validated through immunofluorescence, RT\u2010qPCR, and additional techniques, to collectively identify FLT1 as a pivotal single gene driving ccRCC progression. Our work reveals a FLT1\u2010centered network of related factors, where FLT1 acts as the core single gene, closely associated with key factors VEGFA and AKT1. This network mediates crosstalk between endothelial and epithelial cells: endothelial cells expressing FLT1 alone, AKT1 alone, or co\u2010expressing FLT1\/AKT1 exhibited enhanced malignancy; among epithelial cells, proximal tubular epithelial cells with high VEGFA expression (a factor closely related to FLT1) represented the most aggressive subtype and acted as \u201cpioneer cells\u201d driving tumor progression. This FLT1\u2010centric mechanism is evolutionarily conserved, as validated in mouse single\u2010cell datasets. Clinically, ccRCC patients with low expression of the FLT1\u2010centered network (particularly low FLT1) showed better responses to immunotherapy. For patients with high FLT1 expression, a combination therapy targeting this network\u2014screened via molecular docking and dynamics simulations\u2014may improve prognosis. This includes FLT1 inhibitors (Sorafenib, Regorafenib, Lenvatinib), supplemented by AKT1 inhibitors (Capivasertib) and VEGFA inhibitors (Bevacizumab) to suppress FLT1\u2010associated malignant cell populations.<\/jats:p>","DOI":"10.1096\/fj.202503291rr","type":"journal-article","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T11:05:21Z","timestamp":1776510321000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010Omics and Machine Learning\u2010Uncovered\n                    <scp>FLT1<\/scp>\n                    \u2010Mediated Epithelial\u2010Endothelial Crosstalk in Cellular Senescence Driving Clear Cell Renal Cell Carcinoma Malignancy"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6377-7648","authenticated-orcid":false,"given":"Mouyuan","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Urology The First Affiliated Hospital of 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