Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) exhibits hyperactive mitochondrial metabolism, yet how this rewiring spatially restricts the availability of metabolites for oncogenic signaling and drives systemic metabolic dysregulation in PDAC remains unknown. Here, we identify enhanced mitochondrial α-ketoglutarate (α-KG) sequestration as a key metabolic vulnerability in PDAC. Using multi-omics, preclinical models, and clinical correlation analyses, we identified elevated mitochondrial metabolic gene expression in PDAC. Moreover, higher expression of dihydrolipoamide succinyltransferase (DLST) correlates with poorer PDAC prognosis, suggesting the role of mitochondrial α-KG sequestration in PDAC progression. Targeting mitochondrial respiration with the complex I inhibitor carboxyamidotriazole orotate (CTO) redirected α-KG flux from mitochondrial sequestration, and increased α-KG-dependent m6A demethylation of MYC mRNA and HIF-1α hydroxylation. Combining CTO or α-KG dehydrogenase complex inhibitor devimistat with an α-KG analog (dimethyl α-KG) amplified c-Myc/HIF-1α suppression. Consequently, prolonged CTO exposure downregulated multiple metabolic pathways (glycolysis, pentose phosphate pathway, fatty acid synthesis) regulated by c-Myc/HIF-1α, and significantly delayed PDAC progression in vitro and in vivo. Our work first identify a novel mechanism whereby mitochondrial metabolism drives systemic metabolic dysregulation in PDAC through the sequestration of α-KG, and establishes "redirecting α-KG flux from mitochondrial sequestration" as a strategy to disable PDAC's metabolic adaptability. The orotate salt form of carboxyamidotriazole effectively disrupts mitochondrial α-KG sequestration to suppresses PDAC growth at a dose equivalent to the clinically tested level.