PDPR (pyruvate dehydrogenase phosphatase regulatory subunit) is a mitochondrial regulatory protein that modulates pyruvate dehydrogenase complex activity by decreasing PDP1 sensitivity to magnesium ions, with this inhibition reversible by spermine [UniProt]. PDPR positively regulates pyruvate carboxylation to acetyl-CoA, indicating central importance in glucose metabolism [GO Annotations]. PDPR loss-of-function has emerged as clinically significant across multiple disease contexts. Germline truncating variants in PDPR were identified in a familial papillary thyroid cancer (PTC) pedigree and additional sporadic PTC cases, with PDPR-deficient thyroid cells showing elevated pyruvate dehydrogenase phosphorylation and altered glucose metabolism 1. PDPR was identified as a novel candidate gene in autism spectrum disorder and intellectual disability through whole-exome sequencing of affected families 2, and through recessive gene discovery in consanguineous neurological disorder families 3. A multi-allelic copy number variant at PDPR was strongly associated with pyruvate (p = 4.81 × 10⁻²¹) and alanine levels in population studies 4. Additionally, PDPR copy number variations associated with gut microbiota composition 5, and PDPR was identified as a candidate gene in essential tremor through genome-wide linkage analysis 6. In diffuse large B-cell lymphoma, PDPR upregulation was part of a metabolic gene signature associated with improved outcomes 7. These findings establish PDPR as a metabolic regulator with implications for neurodevelopmental, endocrine, and malignant diseases.