2nd Edition of International Obesity and Metabolism Conference 2026

Abstract

Metabolic homeostasis requires tight coordination between glycolytic flux and cellular redox balance. Disruption of this coupling is increasingly recognized as a central feature of metabolic disorders and cancer. Here, we identify glutathione (GSH), a key intracellular antioxidant, as an endogenous allosteric activator of pyruvate kinase M2 (PKM2), a rate-limiting enzyme in glycolysis. GSH binding stabilizes the active tetrameric conformation of PKM2, thereby enhancing glycolytic flux while simultaneously buffering oxidative stress. Functionally, this metabolic–redox coupling constrains lipid peroxidation and regulates susceptibility to ferroptosis, a form of iron-dependent oxidative cell death driven by lipid peroxides. Integrated functional analyses further indicate that perturbation of this axis, through modulation of GSH availability or PKM2 activity, disrupts redox homeostasis, promotes lipid peroxidation, and sensitizes cells to ferroptotic stress. These findings position PKM2 as a metabolic sensor that integrates nutrient flux with redox control to maintain cellular homeostasis. Importantly, this mechanism may extend beyond cancer and reflect a broader metabolic vulnerability relevant to obesity-associated metabolic dysfunction, where redox imbalance and lipid dysregulation are prominent. In this context, dysregulated PKM2–GSH coupling may contribute to altered lipid oxidative states and impaired metabolic resilience. Together, our study highlights a central metabolic node linking glycolysis, redox regulation, and lipid peroxidation, and suggests potential therapeutic strategies targeting metabolic–redox coupling in metabolic diseases