癌细胞重新调控其代谢途径以满足生物能和生物合成的需要，并维持其氧化还原平衡。在几种人类肿瘤中，Keap1-Nrf2系统通过调节糖醇磷酸途径（PPP）来控制增殖和代谢重编程。然而，正常增殖细胞是否也发生这种代谢重编程尚不清楚。为了确定正常增殖肝细胞的代谢表型，我们通过三种不同的刺激在肝脏中诱导细胞增殖：部分肝切除术（PH）引起肝再生、两种直接促进剂（亚硝酸铅（LN）或三碘甲状腺原氨酸（T3））引起肝组织增生。在LN处理后，呈现Nrf2活化的正常增殖肝细胞出现了癌代谢重编程的典型特征，包括增强的糖酵解、氧化性PPP、核酸合成、NAD+/NADH合成、改变的氨基酸含量以及下调的氧化磷酸化（OXPHOS）。Nrf2的基因缺失抑制了LN诱导的PPP活化并抑制了肝细胞增殖。此外，当通过PH或T3诱导肝细胞增殖时，并不发生Nrf2活化和随之发生的代谢重编程。许多癌细胞的代谢变化也出现在由不良环境刺激引起的正常增殖肝细胞中。Nrf2活化对于将代谢变化与癌代谢重编程的关键组分包括氧化性PPP的活化联系起来至关重要。我们的研究表明，暴露于LN的成熟肝细胞经历了类似癌的代谢重编程，并提供了一个快速和有效的体内模型，用于研究正常和肿瘤性肝细胞之间代谢变化的分子改变的基础。版权所有 © 2023 美国肝病研究学会。

Cancer cells reprogram their metabolic pathways to support bioenergetic and biosynthetic needs and to maintain their redox balance. In several human tumors the Keap1-Nrf2 system controls proliferation and metabolic reprogramming by regulating the pentose phosphate pathway (PPP). However, whether this metabolic reprogramming also occurs in normal proliferating cells is unclear.To define the metabolic phenotype in normal proliferating hepatocytes, we induced cell proliferation in the liver by three distinct stimuli: liver regeneration by partial hepatectomy (PH) and hepatic hyperplasia induced by two direct mitogens, lead nitrate (LN) or triiodothyronine (T3). Following LN treatment, well-established features of cancer metabolic reprogramming including enhanced glycolysis, oxidative PPP, nucleic acid synthesis, NAD+/NADH synthesis and altered amino acid content as well as downregulated oxidative phosphorylation (OXPHOS) occurred in normal proliferating hepatocytes displaying Nrf2 activation. Genetic deletion of Nrf2 blunted LN-induced PPP activation and suppressed hepatocyte proliferation. Moreover, Nrf2 activation and following metabolic reprogramming did not occur when hepatocyte proliferation was induced by PH or T3.Many metabolic changes in cancer cells are shared by proliferating normal hepatocytes in response to a hostile environment. Nrf2 activation is essential for bridging metabolic changes with crucial components of cancer metabolic reprogramming including the activation of oxidative PPP. Our study demonstrates that matured hepatocytes exposed to LN undergo a cancer-like metabolic reprogramming and offers a rapid and useful in vivo model to study the molecular alterations underpinning the differences/similarities of metabolic changes in normal and neoplastic hepatocytes.Copyright © 2023 American Association for the Study of Liver Diseases.