Reductive Stress and Ferroptosis: Linking Insulin Signaling to Metabolic Dysfunction

Reductive stress, characterized by excessive reducing equivalents such as NADH, NADPH, and reduced glutathione (GSH), is increasingly recognized as a pathophysiological counterpart to oxidative stress. Chronic hyperinsulinemia and insulin resistance promote this over-reduced state by increasing glucose flux, pentose phosphate pathway activity and de novo lipogenesis, thereby elevating NADPH pools and reshaping cellular lipid composition. While reducing equivalents are essential for biosynthesis and antioxidant defense, persistent over-reduction disrupts redox balance, mitochondrial function and metabolic flexibility. Paradoxically, this reductive metabolic environment may increase susceptibility to ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and failure of glutathione peroxidase 4 (GPX4). Here, we define how reductive stress becomes deregulated in the context of insulin signaling and insulin resistance, and assess whether antioxidant interventions can mitigate ferroptosis, providing a framework for therapeutic strategies to restore redox balance in metabolic disease.