Roxadustat induces hepatotoxicity in zebrafish embryos via inhibiting Notch signaling

Abstract Roxadustat is a novel and effective small‐molecule inhibitor of hypoxia‐inducible factor prolyl hydroxylase (HIF‐PHI). However, little research has been done on its toxicity to vertebrate embryonic development. In this study, we used zebrafish to assess the effects of roxadustat on early embryonic development. Exposure to 14, 28, and 56 μM roxadustat resulted in abnormal embryonic development in zebrafish embryos, such as shortened body length and early liver developmental deficiency. Roxadustat exposure resulted in liver metabolic imbalance and abnormal liver tissue structure in adult zebrafish. In addition, roxadustat could up‐regulate oxidative stress, and astaxanthin (AS) could partially rescue liver developmental defects by down‐regulation of oxidative stress. After exposure to roxadustat, the Notch signaling is down‐regulated, and the use of an activator of Notch signaling can partially rescue hepatotoxicity. Therefore, our research indicates that roxadustat may induce zebrafish hepatotoxicity by down‐regulating Notch signaling. This study provides a reference for the clinical use of roxadustat.