Bio: Shuyu Zhang, Professor, Chief Scientist of Key Laboratory of Medical Translation of Nuclear Technology, National Health Commission. He has long been engaged in research on tumor radiosensitivity mechanisms and nuclear radiation damage prevention and treatment strategies. He has published more than 150 papers, with more than 80 papers as first author or corresponding author. He has published (co-)corresponding author papers in Cell Mol Immunol, Adv Sci (cover story), Exp Mol Med, Int J Radiat Oncol Biol Phys (Red J) and Radiat Res, among others. He has edited three monographs; led the formulation of one group standard; obtained 26 Chinese invention patents and three U.S. invention patents, and some of the patent achievements have been transformed. He hasrevealed novel mechanisms of radiation damage such as tetrahydrobiopterin metabolism, zinc homeostasis and adipocyte-mediated radioprotection. Some of his achievements have been clinically translated.

Abstract: Genotoxic insults trigger reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary or cutaneous Gch1 knockout in mice aggravated tissue injury following irradiation, whereas Gch1 knock-in mice exhibited attenuated radiation-induced toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could restrict ROS generation. The loss of S-nitrosylation in LDHA after irradiation increased radiosensitivity. In human patients with radiation-induced skin injury, application of BH4 attenuates this injury and better quality of life. Overall, the serious studies showed that GCH1-mediated BH4 biosynthesis played a key role in the ROS cascade and radiosensitivity through LDHA S-nitrosylation, identifying novel therapeutic strategies for the treatment of radiation-induced injury.