Piceatannol reduces radiation-induced DNA double-strand breaks by suppressing superoxide production and enhancing ATM-dependent repair efficiency

• Piceatannol suppresses X-ray induced elevation in superoxide levels • Pre-irradiation PIC treatment reduces DNA double-strand breaks induced by X-rays and heavy ion beams • Post-irradiation PIC treatment increases the efficiency of DNA double-strand break repair via ATM • Post-irradiation PIC treatment inhibits X-ray-induced increase in the level of Senescence-associated beta-galactosidase In contemporary society, humans are susceptible to various radiation-borne hazards, including exposure to therapeutic modalities using low-linear energy transfer (low-LET) radiations (X-rays and γ-rays), natural high-LET radiation sourced from cosmic rays, as well as nuclear accidents such as the Fukushima Daiichi Nuclear Power Plant incident. Therefore, this threat incites an imminent necessity to develop novel radioprotective agents against a wide range of LET radiation and elucidate the underlying molecular mechanisms. This study aimed at assessing the radioprotectivity of Piceatannol (PIC), a potent antioxidant polyphenol present in abundance in passion fruit, by investigating its effects on radiation-induced reactive oxygen species (ROS) production and the consequent DNA double-strand break (DSB) capacity and cellular senescence. Specifically, total ROS was evaluated by DCFDA staining, mitochondrial superoxide by MitoSOX staining, DSB by γ-H2AX immunostaining, and cellular senescence by Senescence-associated-β-galactosidase staining. The results demonstrated that PIC administration prior to exposure to both X-ray and high-LET radiation impeded radiation-induced DSB by suppressing ROS production. Interestingly, post-irradiation PIC treatment did not alter ROS levels but enhanced the efficiency of Ataxia Telangiectasia Mutated (ATM)-mediated DSB repair. Additionally, post-irradiation PIC treatment diminished senescence-associated beta-galactosidase levels, indicating that it hinders cellular senescence. Conclusively, PIC exerts radioprotective effects against a wide range of LET radiation. The study findings validate the potential application of PIC not only as a radical scavenger but also as a novel DSB repair-activating radioprotective agent. Radioprotective effect of piceatannol Pre-irradiation PIC treatment suppresses DSB caused by X-rays and heavy ion beams by reducing ROS. Interestingly, post-irradiation PIC treatment led to more efficient DSB repair via ATM, without ROS reduction. The effect of post-PIC treatment also inhibits cellular senescence.