Comparative Analysis of FLASH and Conventional Radiotherapy: Unveiling the Effect Modulation Mediated by SOD-1 Inhibition

FLASH radiotherapy, characterized by ultra-high dose rates, has emerged as a promising approach to improve the therapeutic index of radiation treatments by reducing normal tissue toxicity while maintaining tumor control comparable to conventional radiotherapy. Despite growing preclinical evidence, the biological mechanisms underlying the so-called “FLASH effect” remain only partially understood. This study investigates the differential biological responses to FLASH and conventional irradiation in tumor and normal cell models, with a specific focus on redox homeostasis and antioxidant defense systems. Cellular viability and clonogenic survival were assessed following irradiation in the presence or absence of the SOD1 inhibitor ATN-224, used to modulate radiation-induced oxidative stress. The results reveal a distinct response between healthy and cancer cells, indicating that redox regulation could plays a central role in the selective normal tissue sparing observed with FLASH irradiation. Overall, these findings support the hypothesis that modulation of oxidative stress contributes significantly to the FLASH effect and provide a mechanistic rationale for its further preclinical investigation and potential clinical translation.