氧化应激调节肝癌的发生，然而，在从肝硬化到肝细胞癌（HCC）的进展过程中，代谢对氧化应激的直接控制的证据一直缺乏。非氧化分支的核糖磷酸途径（PPP）的限速酶转醛酸酐酶（TAL）缺乏限制了小鼠和人类的生长并预置肝硬化和HCC。在这里，我们展示了线粒体氧化应激和从肝硬化到HCC的进展以及对丙氨酚引起的肝脏坏死严重依赖于糖醇还原酶（AR）造成的NADPH耗竭和糖醇积累，而这个酶则保护不受糖醇陷阱限制并在TAL缺乏中生长受限。TAL和AR都被限制在细胞质中，然而，它们的失活以相反的方向扭曲了线粒体氧化还原稳态。结果表明，AR作为PPP的碳循环和NADPH输出的速率控制器对从肝硬化到HCC的疾病进展具有广泛的影响。© 2023该作者，独家许可给斯普林格自然有限公司。

Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), restricts growth and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Both TAL and AR are confined to the cytosol; however, their inactivation distorts mitochondrial redox homeostasis in opposite directions. The results suggest that AR acts as a rheostat of carbon recycling and NADPH output of the PPP with broad implications for disease progression from cirrhosis to HCC.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.