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Oxidative stress activates cellular senescence, induces abnormal glycolysis, and is associated with pyruvate kinase muscle isoform 2 (PKM2) dysfunction; however, the mechanisms linking PK activation to cellular senescence have not been elucidated. We hypothesized that PKM2 activation by TEPP\u201046 could suppress oxidative stress\u2010induced renal tubular cell injury and cellular senescence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>To investigate the effects of PKM2 activation on oxidative stress\u2010induced cellular senescence, we conducted \u03b2\u2010galactosidase staining and western blot analysis on human primary renal tubular cells (pRPTECs) treated with hydrogen peroxide with or without TEPP\u201046. IL\u20106 levels and glycolytic flux were measured. Cell viability and apoptosis were assessed via the MTS assay and caspase 3 cleavage. For in vivo experiments, we utilized CD\u20101<jats:sup><jats:italic>db\/db<\/jats:italic><\/jats:sup> mice, a fibrotic type 2 diabetes model, which exhibit kidney fibrosis. After 4\u2009weeks of TEPP\u201046 intervention, kidney fibrosis and the expression of senescence markers were analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In pRPTECs, hydrogen peroxide increased the number of \u03b2\u2010galactosidase\u2010positive cells, the expression of senescence markers (p16, p21, p53), and p38 phosphorylation; co\u2010incubation with TEPP\u201046 suppressed these alterations. Hydrogen peroxide reduced cell viability, induced apoptosis, mesenchymal alterations, and increased lactate production and IL\u20106 secretion; co\u2010incubation with TEPP\u201046 or a p38 inhibitor mitigated these effects. In CD\u20101<jats:sup><jats:italic>db\/db<\/jats:italic><\/jats:sup> mice, TEPP\u201046 intervention suppressed apoptosis, fibrosis, and tended to reduce the levels of senescence\u2010associated molecules in the kidney.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>PKM2 activation could be a molecular target for protection against senescence\u2010associated organ damage, including diabetic kidney disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jdi.14397","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T11:31:15Z","timestamp":1737545475000},"page":"598-607","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The <scp>PKM2<\/scp> activator <scp>TEPP<\/scp>\u201046 suppresses cellular senescence in hydrogen peroxide\u2010induced proximal tubular cells and kidney fibrosis in <scp>CD<\/scp>\u20101<i><sup><i>db\/db<\/i><\/sup><\/i> mice"],"prefix":"10.1111","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2418-2207","authenticated-orcid":false,"given":"Shin\u2010ichiro","family":"Ishihara","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Internal Medicine Shimane University  Izumo Shimane Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. Imrul","family":"Kayes","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Internal Medicine Shimane University  Izumo Shimane Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8396-2659","authenticated-orcid":false,"given":"Hirofumi","family":"Makino","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Internal Medicine Shimane University  Izumo Shimane Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Internal Medicine Shimane University  Izumo Shimane Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asako","family":"Kumagai","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Internal Medicine Shimane University  Izumo Shimane Japan"},{"name":"Department of Obstetrics and Gynecology Juntendo University  Tokyo 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2711-1539","authenticated-orcid":false,"given":"Daisuke","family":"Koya","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology Kanazawa Medical University  Kahoku District Ishikawa Japan"},{"name":"Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute Kanazawa Medical University  Kahoku District Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9563-502X","authenticated-orcid":false,"given":"Keizo","family":"Kanasaki","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Internal Medicine Shimane University  Izumo Shimane Japan"},{"name":"The Center for Integrated Kidney Research and Advance, Faculty of Medicine Shimane University  Izumo Shimane 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