The pyruvate dehydrogenase complex at the crossroads of cancer metabolism and cell death.

The pyruvate dehydrogenase complex (PDHC) is a key metabolic hub that couples glycolysis-derived carbon flux to the tricarboxylic acid cycle and mitochondrial function. Its activity is regulated by pyruvate dehydrogenase kinases, phosphatases, and lysine acylation, enabling dynamic responses to metabolic and stress signals. In cancer, dysregulation of the PDK-PDHC axis reduces PDH flux, promotes aerobic glycolysis, and enhances adaptation to mitochondrial and oxidative stress, thereby influencing susceptibility to regulated cell death. Recent studies further suggest that PDHC exhibits considerable structural and functional plasticity under hypoxia and redox stress. Growing preclinical and translational evidence indicates that targeting the PDK-PDHC axis may redirect metabolic flux and improve therapeutic responses in selected tumor contexts. This review summarizes current understanding of PDHC regulation, its context-dependent roles in regulated cell death, and the therapeutic potential and challenges of exploiting PDH-related metabolic vulnerabilities in cancer.