Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis. Danio rerio

Selenium, one of a class of selenocysteine-containing proteins (selenoproteins), is an essential micronutrient known for its cancer prevention properties. Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LCMS/ MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels. Overall design: 4 WT zebrafish samples and 4 SepH mutant samples

硒（selenium）作为一类含硒半胱氨酸蛋白质（硒蛋白，selenoprotein）的核心组成成分，是已知具备防癌特性的必需微量营养素。硒蛋白H（Selenoprotein H，SepH）是近年发现的一种核仁氧化还原酶，其具体功能目前尚未完全阐明。本研究证实，seph基因是调控斑马鱼器官发育的必需基因。通过靶向液相色谱-串联质谱（LC-MS/MS）开展代谢轮廓分析，结果显示SepH缺陷会通过降低抗坏血酸与甲硫氨酸的水平、同时升高甲硫氨酸亚砜的含量，破坏氧化还原稳态。转录组分析结果表明，SepH缺陷会诱发炎症反应并激活p53信号通路。因此，seph基因的缺失会使斑马鱼幼体更易受到氧化应激与DNA损伤的影响。最后，本研究证实，成年个体中seph与p53缺陷存在协同作用，可加速胃肠道肿瘤的发生发展。综上，本研究结果证实seph可调控氧化还原稳态并抑制DNA损伤。我们据此提出假设：硒水平较低的研究队列中观察到的癌症风险升高，可能与SepH缺陷存在关联。实验整体设计：4份野生型（wild type，WT）斑马鱼样本与4份SepH突变型斑马鱼样本。