Write a PREreview

FLASH radiotherapy, characterized by ultra-high dose rates, has been shown to reduce normal tissue toxicity while preserving tumor control, yet its underlying mechanism remains unresolved. Existing models based on radiolytic oxygen depletion (ROD) successfully capture dose-rate dependence but fail to explain key experimental features, including threshold-like onset, saturation of the sparing effect, and sensitivity to temporal delivery structure. Here, we propose a minimal mechanistic framework—Memory-modulated Radiolytic Oxygen Depletion (M-ROD)—that extends classical ROD by incorporating a bounded, history-dependent internal state guided by and consistent with coarse-grained reductions of gene regulatory network dynamics, which provide a natural basis for nonlinear activation, saturation, and state transitions. In this model, dose-rate–dependent stress activates a nonlinear biological state that evolves through feedback, decay, and saturation, modulating radiosensitivity alongside oxygen effects. We show that this framework reproduces the defining characteristics of FLASH, including sharp transitions, plateau behavior, and strong dependence on pulse spacing, duty cycle, and irradiation sequence, while reducing to conventional radiobiology under low dose-rate conditions. Importantly, the model predicts that the magnitude of the FLASH effect is governed by the extent of state activation rather than dose rate alone, providing a mechanistic explanation for variability across experiments. These results support the interpretation of FLASH as an emergent state transition in a dynamical biological system and offer experimentally testable predictions that distinguish it from memoryless models.