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Deep identifications of the senescence\u2010specific cellular features are crucial to the better understanding of the survival and maintenance of senescence and the development of novel senolytics against senescent cells. By a global proteomic profiling of senescent human BJ fibroblasts induced by ionizing radiation, 178 cellular proteins with at least 4\u2010fold or greater changes in abundance were identified, representing the cellular landscape of the senescent fibroblasts. Functional enrichments and biological experiments demonstrated that the decreased glucose metabolism, reduced ATP and alpha\u2010KG production, and declined chaperones are the most striking features associated with senescent fibroblasts. Moreover, these proteomic features are closely correlated with their transcription alterations confirmed by RT\u2010PCR. Respectively, inhibiting pyruvate dehydrogenase (critical enzyme to supply acetyl\u2010CoA to TCA cycle) or glutaminase GLS1 (crucial enzyme to supplement TCA cycle intermediate alpha\u2010KG) or inhibiting Hsp90 (important member of chaperones) led to the selective killing of senescent fibroblasts, indicating the essential roles of the TCA cycle or chaperones in the survival and maintenance of cellular senescence. Most importantly, co\u2010inhibiting the TCA cycle and Hsp90 gave rise to the enhanced selective killing of senescent fibroblasts as well as the therapy\u2010induced senescent cancer cells and the alleviation of physical dysfunctions in aged mice, suggesting the synergistic regulation of cellular senescence by the TCA cycle and chaperones. Thus, our profiling revealed key cellular features for the survival and maintenance in senescent normal cells, demonstrating that pyruvate dehydrogenase is a novel and potent senolytic target for the selective elimination of senescence.<\/jats:p>","DOI":"10.1111\/acel.70434","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:25:50Z","timestamp":1772987150000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Decreased Glucose Metabolism and Declined Chaperones Are Unique Features Required for the Survival of Senescent Fibroblasts and Pyruvate Dehydrogenase Is a Potent Senolytic Target"],"prefix":"10.1111","volume":"25","author":[{"given":"Mingzhu","family":"Zhang","sequence":"first","affiliation":[{"name":"The Laboratory of Medical Genetics, College of Basic Medicine Harbin Medical University  Harbin 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