A thermodynamic constraint on GPx4 flux links glutathione redox state to ferroptotic commitment

Ferroptosis is a non-accidental form of cell death driven by lipid peroxidation and critically controlled by the selenoenzyme Glutathione Peroxidase 4 (GPx4). By integrating molecular modeling, redox thermodynamics, and enzymatic evidence, we propose that ferroptosis is governed by the redox potential of the glutathione couple, elevating current mechanistic descriptions to a quantitative physical-chemical framework. The terminal step of the GPx4 catalytic cycle-responsible for enzyme regeneration and oxidized glutathione (GSSG) formation-is intrinsically endergonic, and its driving force declines continuously as the glutathione redox potential becomes less reducing. As a result, GPx4 activity decreases linearly in accordance with Nernstian principle, independently of discrete inhibitory events. Within this framework, ferroptosis is not initiated by a discrete molecular trigger or canonical signaling cascade; rather, it emerges when a critical biological threshold is surpassed, such that GPx4-dependent detoxification capacity is no longer sufficient to counteract ongoing lipid peroxidation within a given pro-oxidant context. Thus, a discrete cell-death outcome executed by GSSG emerges from the continuous variation of a thermodynamic control variable. This mode of regulation is unique to selenium chemistry and provides a physical-chemical rationale for the indispensability of selenocysteine in the redox control of cellular life and death.