PIK‐III‐Mediated Elevation of Thiamine Re‐Sensitises Renal Cell Carcinoma to Cuproptosis via Activating PDHA1

ABSTRACT Cuproptosis, a copper‐dependent cell death mechanism driven by tricarboxylic acid (TCA) cycle collapse, shows limited efficacy in hypoxic or glycolytic renal cell carcinoma (RCC). Here, through systematic screening of 688 glycolysis inhibitors combined with elesclomol (ES), we identified PIK‐III as a potent cuproptosis sensitiser. Multi‐omics analysis revealed that PIK‐III restores sensitivity by rewiring thiamine metabolism. Mechanistically, PIK‐III induces macropinocytosis, enabling thiamine uptake to replenish thiamine pyrophosphate (TPP), which activates pyruvate dehydrogenase E1‐alpha 1 (PDHA1) and redirects pyruvate into the TCA cycle. Concurrently, ES‐induced DLAT oligomerisation disrupts TCA flux, creating a metabolic crisis. In vivo, PIK‐III synergises with ES to suppress tumour growth in xenograft and patient‐derived models without systemic toxicity. Our work uncovers a metabolic vulnerability in cuproptosis‐resistant RCC and positions PIK‐III as a therapeutic candidate to overcome resistance via dual targeting of thiamine transport and mitochondrial dysfunction.