Nanosecond laser-driven proton FLASH spares normal tissue cells by sustaining mitochondrial homeostasis and attenuating ferroptosis

Abstract Radiotherapy’s clinical utility remains fundamentally constrained by the collateral damage to healthy tissues. Ultra-high-dose-rate (UHDR) irradiation, or, FLASH-radiotherapy (FLASH-RT) has emerged as a transformative paradigm to mitigate such toxicity. However, the biological effects of FLASH-RT on the high-efficiency of tumor killing and normal tissue sparing remain poorly understood. In this work, we utilized a petawatt-class laser-plasma acceleration (LPA) platform to deliver discrete 12.9-nanosecond proton pulses at an extreme instantaneous dose rate of 1.94×107 Gy/s. This temporal singularity achieved a profound sparing effect in normal bronchial epithelial cells, evidenced by a nine-fold reduction in the lethal α coefficient (from 0.47 to 0.05 Gy-1), while maintaining full tumoricidal potency against lung adenocarcinoma. Mechanistically, we demonstrated that LPA-FLASH could effectively bypass the ATF3-mediated stress response and circumvent the subsequent ferroptotic cascade. This molecular evasion could preserve the mitochondrial cristae integrity and trigger an adaptive bioenergetic ATP surge—a hallmark of metabolic resilience exclusively in healthy tissue cells. Therefore, our findings identify ferroptosis-mediated mitochondrial integrity as a unifying framework for selective normal-tissue protection at the physical limits of radiation delivery, and establish LPA-FLASH-RT as a potent, compact modality for next-generation oncology. Competing Interest Statement The authors have declared no competing interest.