A previous conceptual framework proposed the pulsed administration of exogenous reducing equivalents as a metabolic intervention exploiting differential redox-buffering capacity between transformed and healthy cells (M. Freschi, 2026, preprint). That framework rested on a postulated, qualitative asymmetry in cellular tolerance to reductive stress, without articulating the distinct physiological routes through which the asymmetry would operate or the conditions under which each route would dominate. The present work proposes such an articulation. It is hypothesized that under sustained reductive perturbation, tumor-selective vulnerability arises from the convergent action of four mechanisms operating in parallel, each with its own profile of relevance across operational regimes: (i) a structural asymmetry between healthy and tumor microvasculature with respect to oxygen recruitment under elevated demand, predicted to translate into differential mitochondrial NADH oxidation capacity once perturbation increases local oxygen consumption; (ii) progressive saturation of extracellular electron-acceptor pools, constraining the cellular pathways for redox-equivalent disposal (ECTO-NOX-mediated electron export, MCT-mediated lactate efflux, gap-junction-mediated redox sharing); (iii) transient attenuation of the chronic oxidative load characteristic of the tumor microenvironment, with potential immunometabolic consequences for tumor-infiltrating immune cells; and (iv) chemically specific propagation of the perturbation across the plasma membrane via membrane-permeable reduced species (notably molecular hydrogen, reduced cysteine, reduced metal centers), generated once extracellular acceptor reserves are exhausted. These four mechanisms converge on a common endpoint — exhaustion of intracellular redox-disposal capacity beyond compensatory threshold — through routes whose relative weight depends on perturbation intensity, duration, and modality. The framework yields multiple falsifiable predictions, including the inverse correlation of response with baseline tumor perfusion, accessible through standard imaging modalities (DCE-MRI, perfusion CT, FDG-PET). The framework is presented at the level of physiological and thermodynamic principle; specific implementation modalities are deliberately left abstract.
Marco Freschi (Tue,) studied this question.