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Here, through systematic screening of 688 glycolysis inhibitors combined with elesclomol (ES), we identified PIK\u2010III as a potent cuproptosis sensitiser. Multi\u2010omics analysis revealed that PIK\u2010III restores sensitivity by rewiring thiamine metabolism. Mechanistically, PIK\u2010III induces macropinocytosis, enabling thiamine uptake to replenish thiamine pyrophosphate (TPP), which activates pyruvate dehydrogenase E1\u2010alpha 1 (PDHA1) and redirects pyruvate into the TCA cycle. Concurrently, ES\u2010induced DLAT oligomerisation disrupts TCA flux, creating a metabolic crisis. In\u00a0vivo, PIK\u2010III synergises with ES to suppress tumour growth in xenograft and patient\u2010derived models without systemic toxicity. Our work uncovers a metabolic vulnerability in cuproptosis\u2010resistant RCC and positions PIK\u2010III as a therapeutic candidate to overcome resistance via dual targeting of thiamine transport and mitochondrial dysfunction.<\/jats:p>","DOI":"10.1111\/cpr.70101","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T10:19:59Z","timestamp":1753957199000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>PIK<\/scp>\n                    \u2010\n                    <scp>III<\/scp>\n                    \u2010Mediated Elevation of Thiamine Re\u2010Sensitises Renal Cell Carcinoma to Cuproptosis via Activating\n                    <scp>PDHA1<\/scp>"],"prefix":"10.1111","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1491-1950","authenticated-orcid":false,"given":"Dongdong","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Urology The Fifth 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