Dual Metabolic Blockade in Pancreatic Cancer: Potent Anticancer Activity of Mitochondria-Targeted Glycolysis and OXPHOS Inhibitors

Abstract Simultaneous targeting of glycolysis and oxidative phosphorylation (OXPHOS) is an effective strategy for overcoming the metabolic plasticity of pancreatic ductal adenocarcinoma (PDAC). In this study, we present compound 14c, a rationally designed, mitochondria-targeted small molecule that disrupts PDAC energy metabolism. Compound 14c markedly inhibited PDAC cell glycolysis and mitochondrial function, as evidenced by the PDKs inhibition and the downregulation of OXPHOS-associated proteins, including SDHB and SIRT3, in vitro and in vivo. Mechanistically, 14c induced ferroptotic cell death, accompanied by lipid peroxidation, redox imbalance, and mitochondrial dysfunction. Importantly, 14c also elicited hallmarks of immunogenic cell death (ICD), including calreticulin exposure and HMGB1 release. In a syngeneic PANC02 model, 14c suppressed tumor growth with minimal systemic toxicity and recapitulated the metabolic inhibition and ICD-associated phenotypes observed in vitro. These findings support that 14c could be used as a dual metabolic inhibitor and ICD inducer in PDAC therapy.