Unraveling the Redox Mechanisms Underlying FLASH Radiotherapy: Critical Dose Thresholds and NRF2-Driven Tissue Sparing

Yan Zhang; Chenyang Huang; Ankang Hu; Yucheng Wang; Yixun Zhu; Wanyi Zhou; Jiaqi Qiu; Jian Wang; Qibin Fu; Tuchen Huang; Hao Zha; Wei Wang; Junli Li

arXiv · 2508.20510

Unraveling the Redox Mechanisms Underlying FLASH Radiotherapy: Critical Dose Thresholds and NRF2-Driven Tissue Sparing

Yan Zhang·Chenyang Huang·Ankang Hu·Yucheng Wang·Yixun Zhu·Wanyi Zhou·Jiaqi Qiu·Jian Wang·Qibin Fu·Tuchen Huang·Hao Zha·Wei Wang·Junli Li

View original source ↗Read source document ↗Export metadata ↓

Abstract

FLASH radiotherapy (FLASH-RT) achieves tumor control comparable to conventional dose-rate irradiation (CONV-RT) while significantly reducing radiation damage to normal tissues. However, the physical conditions triggering the FLASH sparing effect remain unclear, and mechanisms related to oxidative stress and redox regulation are poorly understood. This study utilizes a murine acute intestinal toxicity model to investigate how beam parameters influence the FLASH sparing effect and tumor control using innovative FLASH-RT and CONV-RT combined irradiation. Results demonstrate for the first time that a substantially reduced FLASH dose can still elicit sparing effect, provided a total dose threshold is met. Kinetic simulation and experimental validation demonstrate that FLASH-RT enhances peroxyl radical recombination, reducing reactive oxygen species (ROS) and malondialdehyde levels. Antioxidant interventions further confirm the essential role of free radicals. RNA sequencing and molecular analyses reveal that FLASH-RT activates the nuclear factor E2-related factor 2 (NRF2) antioxidant pathway while suppressing extracellular signal-regulated kinases (ERK) signaling, thereby enhancing cellular redox defenses, reducing apoptosis, and mitigating ROS-mediated tissue injury. These findings highlight the feasibility of optimizing the FLASH-RT therapeutic window through redox modulation and provide a foundation for developing free radical-targeted strategies to improve its therapeutic efficacy.

Explore related subjects

physics.med-ph

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Yan Zhang, Chenyang Huang, Ankang Hu, Yucheng Wang, Yixun Zhu, Wanyi Zhou, Jiaqi Qiu, Jian Wang, Qibin Fu, Tuchen Huang, Hao Zha, Wei Wang, Junli Li. 2025-08-28. Unraveling the Redox Mechanisms Underlying FLASH Radiotherapy: Critical Dose Thresholds and NRF2-Driven Tissue Sparing. https://arxiv.org/abs/2508.20510

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related papers

arXiv2026

Prediction of biological radiation effects based on ionization clusters (nanodosimetry)

This article reviews approaches that link the formation of ionization clusters in nanometric volumes to radiobiological effectiveness. The corresponding models were developed as the field of nanodosimetry developed. Some address early biological radiation effects, such as DNA damage, while most aim to predict cell survival or inactivation. The models also differ in the nanodosimetric quantities considered, with many based on the probability distribution of ionization cluster formation in a single target. Some models account for the synergistic effects of pairs of ionization clusters formed in different targets. Several models feature macroscopic aggregation frameworks based on particle fluence, which are proposed for use in radiotherapy treatment planning, particularly in ion-beam radiotherapy. The models are presented here using harmonized terminology and notation for nanodosimetric quantities. An extension of the conceptual framework of nanodosimetry is also discussed. This extension transitions from a target-centered description to a track-centered description. It also introduces nanodosimetry-based analogs of dosimetric concepts, such as dose and linear energy transfer. This paper traces and summarizes the historical development of nanodosimetry-based biological effect models and discusses conceptual aspects of the models to reveal their underlying assumptions and the extent to which they are mechanistic or merely elucidate correlations. Eventually, an attempt is made to identify the key open questions in this field that still need to be addressed.

physics.med-ph↗

arXiv2026

Contextual Cellular Growth (ConCeG) of neural cells for realistic grey matter tissue generation for diffusion MRI simulations

Accurate interpretation of diffusion magnetic resonance imaging (dMRI) signals in grey matter (GM) remains challenging due to the complex, heterogeneous, and densely packed cellular environment. Numerical phantoms provide a controlled framework for investigating the relationship between microstructure and diffusion signals, yet existing approaches often lack the morphological realism and multi-cellular organisation required to faithfully represent GM tissue. In this work, we introduce Contextual Cellular Growth (ConCeG), a generative framework for creating individual cells or constructing dense, three-dimensional, multi-cellular GM substrates informed by real neuronal and glial morphologies. The method combines topological neuron synthesis with a spatially constrained growth network, allowing for the controlled generation of heterogeneous cellular environments with realistic intra- and extracellular compartments. Synthetic cells are generated using morphological and topological characteristics derived from biological reconstructions. We validate the framework through comparisons of structural features with real cellular data, demonstrating strong agreement in branch order, length, angle, and tortuosity distributions. Power spectrum analysis further shows that both intracellular compartments reproduce the spatial correlations observed in biological tissue. Together, these results show ConCeG provides a biologically grounded framework for generating grey matter substrates suitable for large scale diffusion MRI simulation.

physics.med-ph↗

arXiv2026

Magnetic Field of Firing Neuron in Humans: Measurable by Quantum Sensing MRI?

Firing neurons generate action potentials that propagate along axons to transmit signals supporting cognitive functions. These electrical currents generate magnetic fields, yet direct detection of these neuronal magnetic fields by MRI remains elusive. This Mini Review investigates why this goal has been proven difficult to achieve and whether an emerging approach, quantum sensing MRI, can overcome the challenge.

physics.med-ph↗