Mitigating the side effects of conventional radiotherapy: deep examination of the FLASH effect on human healthy bronchial epithelial cell line.

Lung cancer is the second leading cause of cancer-related deaths. Treatment based on conventional radiotherapy often results in severe side effects, such as pulmonary fibrosis, a fatal and untreatable condition. FLASH radiotherapy is an emerging technique that aims to minimize damage to healthy tissue while maintaining similar tumour-killing effectiveness by delivering ultra-high dose rate radiation, needed to trigger the so-called "FLASH effect". This study explored the molecular basis of the electron FLASH effect in healthy human bronchial epithelial cells. Cells were irradiated using a linear accelerator both with conventional and FLASH radiotherapy to evaluate differences in oxidative stress, cell viability, apoptosis, and early fibrosis markers. FLASH administration resulted in lower ROS production and consistent reduction of macromolecules' oxidation, lower cell death and the absence of a cell cycle arrest, specifically with the lowest dose. Moreover, FLASH-exposed cells exhibited reduced expression of early fibrosis markers like vimentin. These findings reveal a clear FLASH effect in healthy cells, with reduced fibrosis, suggesting free radicals' involvement in radiotherapy outcomes.