Anthraquinone Rhein Mitigates Heavy Ion Radiation-Induced Lung Injury by Maintaining Thioredoxin Reductase/Thioredoxin (TrxR/Trx) Redox Homeostasis

While heavy ion radiation, particularly carbon-ion therapy exploits high linear energy transfer (LET) radiation for precise tumor targeting through DNA/oxidative damage, its concomitant toxicity to adjacent normal tissues remains a critical limitation. Here, we investigated the radioprotective potential of Rhein, a natural anthraquinone derivative, in ionizing radiation-irradiated lung cells and murine models. In vitro, Rhein pretreatment enhanced cell viability and clonogenic survival, mitigated DNA damage (evidenced by reduced γ-H2AX foci and micronucleus formation), attenuated reactive oxygen species (ROS) generation, and maintained mitochondrial membrane potential during X-irradiation and carbon-ion treatment. Molecular docking analysis indicated that Rhein binding to wild-type or mutant TrxR occurred without substantially changing docking sites, suggesting that Rhein likely interacts with a stable binding pocket distinct from the active sites. Significantly, the protective action of Rhein was not evident in thioredoxin reductase knockdown cells, suggesting the participation of an intact thioredoxin reductase/thioredoxin (TrxR/Trx) system. In <i>vivo</i>, Rhein pretreatment extended survival of heavy-ion radiation-irradiated mice and corrected the redox homeostasis of lung tissue by up-regulating reduced thioredoxin (Red-Trx) and down-regulating oxidized thioredoxin (Ox-Trx). These findings suggest that Rhein offers radioprotection against heavy-ion radiation-induced lung damage through modulating TrxR/Trx redox homeostasis, which suggests its potential as a radioprotective agent in heavy-ion therapy.