The liver exhibits a remarkable capacity to regenerate following injury. Despite this unique attribute, toxic injury is a leading cause of liver failure. The temporal processes by which the liver senses injury and initiates regeneration remain unclear. Here, we developed a transgenic zebrafish model wherein hepatocyte-specific expression of uracil phosphoribosyltransferase (UPRT) enabled the implementation of SLAM-ITseq to investigate the nascent transcriptome during initiation of liver injury and regeneration. Using this approach, we identified a rapid metabolic transition from the fed to the fasted state that was followed by induction of the nuclear erythroid 2-related factor (Nrf2) antioxidant program. We find that activation of Nrf2 in hepatocytes is required to induce the pentose phosphate pathway (PPP) and improve survival following liver injury. Mechanistically, we demonstrate that inhibition of the PPP disrupts nucleotide biosynthesis to prevent liver regeneration. Together, these studies provide fundamental insights into the mechanism by which early metabolic adaptation to injury facilitates tissue regeneration.

肝脏在损伤后表现出非凡的再生能力。尽管具有这种独特的属性，但毒性损伤是肝衰竭的主要原因。肝脏感知损伤并启动再生的时间过程仍不清楚。在这里，我们开发了一种转基因斑马鱼模型，其中尿嘧啶磷酸核糖基转移酶（UPRT）的肝细胞特异性表达使得能够实施SLAM-ITseq来研究肝损伤和再生开始期间的新生转录组。使用这种方法，我们确定了从进食状态到禁食状态的快速代谢转变，随后诱导核红细胞 2 相关因子 (Nrf2) 抗氧化程序。我们发现肝细胞中 Nrf2 的激活需要诱导戊糖磷酸途径 (PPP) 并提高肝损伤后的存活率。从机制上讲，我们证明抑制 PPP 会破坏核苷酸生物合成，从而阻止肝再生。总之，这些研究为早期代谢适应损伤促进组织再生的机制提供了基本见解。