Honokiol protects against heavy-ion radiation-induced oxidative damage via the thioredoxin system

Exposure to radiation from environmental, medical, and occupational sources is a serious health hazard, with genomic instability and oxidative stress being the major culprits. Honokiol (HKL), a biphenol derived from Magnolia plants, has been shown to possess strong antioxidant activity. In this study, we investigated the radioprotective effect of HKL against ionizing radiation-induced damage, with its capacity to modulate the thioredoxin reductase/thioredoxin (TrxR/Trx) redox system being the focus of investigation. Specifically, human bronchial epithelial cells (BEAS-2B) and female C57BL/6 mice were exposed to 4 Gy X-ray or 2 Gy carbon ions for all experiments except mouse survival analysis, where 8.0 Gy X-ray or 5.0 Gy carbon ions were used. HKL was administered at 5.00 μM for cell experiments and 15.00 mg/kg for animal experiments. A comprehensive research framework utilizing in vitro cellular models and in vivo models, we demonstrated that HKL pretreatment greatly increased cell viability, inhibited DNA damage, and relieved reactive oxygen species (ROS) accumulation in irradiated cells. Molecular docking of TrxR with its specific selenocysteine (Sec498) active site and biochemical analyses identified that HKL stabilizes the TrxR/Trx redox system without direct inhibition of TrxR catalytic activity. HKL pretreatment also reduced the bystander effect and enhanced survival in irradiated mice, with significant protective effects observed specifically in lung tissues. These findings suggest its value as a radioprotective agent. This study elucidates the molecular mechanism through which HKL confers radiation protection by targeting the TrxR/Trx system for the first time. These findings highlight the radioprotective potential of HKL via TrxR/Trx system modulation, and provide a rationale for further preclinical evaluation.