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

Abstract

Radiotherapys 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 1.94x107 Gy/s. This temporal singularity achieved a profound sparing effect in normal bronchial epithelial cells, evidenced by a nine-fold reduction in the lethal 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.