Unraveling the effects of FLASH and conventional irradiation on retinal pigment epithelial cells: in vitro and in vivo studies

The retinal pigment epithelium (RPE) is a fundamental monolayer of pigmented cells that supports visual function, situated between the neural retina and choroidal blood vessels. Radiotherapy is a common treatment for ocular tumors such as uveal melanoma; however, the RPE is inevitably exposed to radiation during treatment. FLASH radiotherapy, characterized by ultra-high dose-rates, has emerged as a promising approach to minimize normal tissue toxicity while maintaining tumor control. Despite its potential, few preclinical studies have explored the effects of FLASH irradiation on the RPE, and no studies have directly compared FLASH with conventional (CONV) radiotherapy in this context. Using a LINAC capable of switching between FLASH and CONV irradiation, we here address the radiobiological effects on ARPE-19 cells, an in vitro RPE model, and the RPE of living mice. FLASH treatment demonstrated protective effects on ARPE-19 cells, enhancing cell viability and modulating cytokine expression (e.g., IL-6, IL-8). Furthermore, RPE tissue exhibited dose-dependent radiation sensitivity, with FLASH-irradiated mice performing better than CONV-treated ones. These findings indicate that FLASH radiotherapy may protect the RPE during ocular tumor treatment and provide insights into tissue-specific radiation sensitivity in the eye, supporting further research into its clinical applications.