biostudies-literaturePeng JU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesUniversity of Kentucky (UK)University of KentuckyU.S. Department of DefenseU.S. Department of Defense (United States Department of Defense)NCI NIH HHSU.S. Department of Health & Human Services | National Institutes of Health (NIH)U.S. Department of Health & Human Services | National Institutes of HealthNIGMS NIH HHS4190-4204https://www.ebi.ac.uk/biostudies/studies/S-EPMC12503065biostudies-literatureUnknown44(43)Although the involvement of polo-like kinase 1 (PLK1) in metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis has been previously described, the underlying molecular mechanism remains unclear. Pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate into acetyl-CoA, the starting material for the tricarboxylic acid (TCA) cycle. In a companion study by Zhang et al., we demonstrated that PLK1 phosphorylation of PDHA1 at threonine 57 (PDHA1-T57) drives its protein degradation via mitophagy activation. Using a stable-isotope resolved metabolomics (SIRM) approach, we now show that PLK1 phosphorylation of PDHA1-T57 results in metabolic reprogramming from OXPHOS to glycolysis. Notably, cells mimicking PDHA1-T57 phosphorylation rely more on the aspartate-malate shuOncogenePLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer.PMC12503065P30CA177558R01 CA264652CA157429P30 GM127211CA264652CA256893DoD-HT9425-24-1-0442P30 CA177558R01 CA272483CA272483R01 CA256893R01 CA196634R01 CA157429CA196634Liu XLiu JLi ZWang RZhang YRao XAllison DBKatz WKong YPeng JZhang QfalsePLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer.Although the involvement of polo-like kinase 1 (PLK1) in metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis has been previously described, the underlying molecular mechanism remains unclear. Pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate into acetyl-CoA, the starting material for the tricarboxylic acid (TCA) cycle. In a companion study by Zhang et al., we demonstrated that PLK1 phosphorylation of PDHA1 at threonine 57 (PDHA1-T57) drives its protein degradation via mitophagy activation. Using a stable-isotope resolved metabolomics (SIRM) approach, we now show that PLK1 phosphorylation of PDHA1-T57 results in metabolic reprogramming from OXPHOS to glycolysis. Notably, cells mimicking PDHA1-T57 phosphorylation rely more on the aspartate-malate shu2025-01-01T00:00:00Z2025 Nov2026-06-04T14:49:33.093Z2026-05-10T03:11:35.695ZS-EPMC125030654095795010.1038/s41388-025-03571-1