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How glycolytic enzymes contribute to metabolic stress tolerance in ccRCC remains incompletely understood. We investigated the role of the glycolytic enzyme 2,3-bisphosphoglycerate mutase (BPGM) using human tumor specimens, siRNA-mediated gene silencing, functional cell-based assays, and transcriptomic profiling. Epigenetic stress was induced using Vorinostat as a pan-histone deacetylase inhibitor. BPGM expression was consistently elevated in human ccRCC compared with adjacent normal kidney tissue. A498 cells exhibited high basal BPGM levels and limited sensitivity to Vorinostat, whereas BPGM depletion increased cellular stress responses and reduced proliferative capacity. Despite similar phenotypic outcomes, BPGM silencing and Vorinostat treatment triggered distinct transcriptional programs. While HDAC inhibition induced widespread transcriptional changes, BPGM loss elicited a focused stress-associated response, consistent with activation of the unfolded protein response, increased lipid peroxidation, and induction of ER stress-associated genes. Our data identify BPGM as a metabolic player contributing to stress-adaptive transcriptional states in ccRCC and suggest that targeting metabolic stress adaptation may complement epigenetic strategies in renal cancer.<\/jats:p>","DOI":"10.3390\/cells15070633","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T15:14:43Z","timestamp":1775142883000},"page":"633","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["2,3-Bisphosphoglycerate Mutase (BPGM), a Metabolic Player Shaping Stress-Adaptive Transcriptional States in Clear Cell Renal Cell Carcinoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8607-7185","authenticated-orcid":false,"given":"Philipp N.","family":"Becker","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Translationale Physiologie (CCM), Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie 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