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Nanosecond Laser-Driven Proton FLASH Spares Normal Tissue Cells by Sustaining Mitochondrial Homeostasis and Attenuating Ferroptosis

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Communication Open Access

Nanosecond Laser-Driven Proton FLASH Spares Normal Tissue Cells by Sustaining Mitochondrial Homeostasis and Attenuating Ferroptosis

Changsheng Shao 1,† Yu Zhang 2,† Pengzhi He 3,† Xin Yu 1,4 Wenjie Peng 2,5 Junfeng Chen 2,5 Haotian Hu 2,5 Yiying Wang 3 Mei Xiao 6 Chao Liu 7 Li Sui 8 Tianyuan Dai 9 Xiangkui Mu 10 Xianghong Jia 3,11,* Jian-Hui Bin 2,5,* Qing Huang 1,4,*,‡

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1
Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
2
State Key Laboratory of Ultra-Intense Laser Science and Technology, Shanghai Institute of Optics and Fine Mechanics, Chinese Academy of Sciences, Shanghai 201800, China
3
Shandong Key Laboratory of Space Environment and Exploration Technology, School of Space Science and Technology, Shandong University, Weihai 264209, China
4
Science Island Branch of Graduate School, University of Science and Technology of China, Hefei 230052, China
5
Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 101408, China
6
Shanghai Proton and Heavy Ion Center, Shanghai 4365, China
7
School of Biomedical Engineering, Anhui Medical University, Hefei 230032, China
8
Department of Nuclear Physics, China Institute of Atomic Energy, Beijing 102413, China
9
Department of Radiation Oncology Physics and Technology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
10
Shandong Proton, Heavy Ion and Neutron Therapy Center, Shandong First Medical University Affiliated Tumor Hospital, Jinan 250117, China
11
College of Science, Xizang University, Lhasa 850000, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
This author is the primary corresponding author.

Received: 12 April 2026 Revised: 18 May 2026 Accepted: 22 June 2026 Published: 13 July 2026

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© 2026 The authors. This is an open access article under the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

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iMed 2026, 1(1), 10006; DOI: 10.70322/iMed.2026.10006
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.
Keywords: FLASH-radiotherapy (FLASH-RT); Laser-plasma acceleration (LPA); Mitochondrial integrity; Ferroptosis; Normal tissue cells sparing

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