A Dynamical Model of Glutathione Homeostasis in G6PD Deficiency and NRF2-Activated Non-Small Cell Lung Cancer

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Background Antioxidant supplementation helps some patients, harms specific subgroups (G6PD deficiency, hereditary hemochromatosis, KEAP1-mutant lung cancer), and does little in most. Some of this heterogeneity reflects conserved biology; some reflects noise (weak subgroup analyses, imperfect biomarkers, post-hoc interpretation). No mechanistic framework has yet produced quantitative, falsifiable forward predictions for the GSH-coupled subset. Methods We build a three-variable dynamical model of GSH homeostasis (a finite GSH pool, saturable NADPH-dependent regeneration, and a slow NRF2-controlled regeneration capacity), calibrate the static-capacity (erythrocyte) case against published kinetics, and stress-test the dynamic-capacity (nucleated-cell) case computationally. Results — calibrated Without fitting any parameter to clinical data, the model recovers the established G6PD severe-deficiency single-exposure contraindications; the ordering of threshold-crossing by severity class is robust to ±50% variation in any single parameter. Results — falsifiable prediction For adjunctive NAC in KEAP1-mutant or NRF2-IHC-high NSCLC on platinum chemotherapy, the model generates a prospective, pre-specified prediction stratified by evidential strength. Direction (harm) and subgroup selectivity (concentrated in the NRF2-active stratum) are framework-derived; the magnitude (progression hazard ratio, central estimate 1.55) is explicitly conditional and reported across a sensitivity range. A within-trial partial flux-proxy biomarker (plasma 8-oxo-dG) and explicit falsification thresholds are committed in advance. The design is a biomarker-stratified randomized trial whose scale sits between conventional Phase II and Phase III. Conclusions One mathematical object, three regimes, two failure modes. The G6PD result is independently calibrated; the NSCLC result is a falsifiable extrapolation. This split between calibrated result and forward prediction is the central scientific commitment.