转醛酮醇酶缺乏易导致从肝硬化到肝细胞癌（HCC）的慢性肝病。从肝硬化过渡到肝癌发生依赖于线粒体氧化应激，该应激由胞质糖醛代谢通过糖醇磷酸戊糖途径（PPP）控制。HCC的进展在很大程度上依赖于NADPH耗竭和糖醇还原酶（AR）引起的聚醇积累，而该酶则能防止PPP中的碳陷阱和TAL缺陷引起的生长限制。虽然AR失活可以阻止对肝癌的敏感性，但会加强生长受限、非氧化PPP分支中的碳陷阱，并且无法逆转葡萄糖6-磷酸（G6P）和肝硬化的耗竭。在本研究中，我们展示了TAL-AR轴的失活导致代谢应激，其特征为线粒体嗜食减少、整体自噬增强、机械靶向雷帕霉素（mTOR）的活化、糖基化和磷脂酶1（PON1）的分泌减少、抗磷脂自身抗体（aPL）的产生、CD161+ NK细胞的丧失，以及CD38+ Ito细胞的扩增。这些细胞对体内雷帕霉素治疗有响应。因此，本研究确定了在TAL缺陷中自身免疫引起肝硬化的依赖于mTOR的糖基化、PON1分泌和aPL产生作为调节检查点。版权所有 © 2023 Elsevier Ltd. 保留所有权利。

Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is 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. Although AR inactivation blocked susceptibility to hepatocarcinogenesis, it enhanced growth restriction, carbon trapping in the non-oxidative branch of the PPP and failed to reverse the depletion of glucose 6-phosphate (G6P) and liver cirrhosis. Here, we show that inactivation of the TAL-AR axis results in metabolic stress characterized by reduced mitophagy, enhanced overall autophagy, activation of the mechanistic target of rapamycin (mTOR), diminished glycosylation and secretion of paraoxonase 1 (PON1), production of antiphospholipid autoantibodies (aPL), loss of CD161+ NK cells, and expansion of CD38+ Ito cells, which are responsive to treatment with rapamycin in vivo. The present study thus identifies glycosylation and secretion of PON1 and aPL production as mTOR-dependent regulatory checkpoints of autoimmunity underlying liver cirrhosis in TAL deficiency.Copyright © 2023 Elsevier Ltd. All rights reserved.