Hepatocellular carcinoma (HCC) is a longstanding issue in clinical practice and metabolic research. New clues in better understanding the pathogenesis of HCC might relate to the metabolic context in patients with citrin (aspartate-glutamate carrier 1) deficiency (CD). Because citrin-deficient liver (CDL) is subject to HCC, it represents a unique metabolic model to highlight the mechanisms of HCC promotion, offering different angles of study than the classical metabolic syndrome/obesity/non-alcoholic fatty liver disease (NAFLD)/HCC study axis. In turn, the metabolic features of HCC could shed light on the pathogenesis of CDL. Among these, HCC-induced re-activation of aralar-1 (aspartate-glutamate carrier 2), physiologically not expressed in the adult liver, might take place in CDL, so gene redundancy for mitochondrial aspartate-glutamate carriers would be exploited by the CDL. This proposed (aralar-1 re-activation) and known (citrate/malate cycle) adaptive mechanisms may substitute for the impaired function in CD and are consistent with the clinical remission stage of CD and CD improvement by medium-chain triglycerides (MCT). However, these metabolic adaptive benefits could also promote HCC development. In CD, as a result of PPARα down-regulation, liver mitochondrial fatty acid-derived acetyl-CoA would, like glucose-derived acetyl-CoA, be used for lipid anabolism and fuel nuclear acetylation events which might trigger aralar-1 re-activation as seen in non-CD HCC. A brief account of these metabolic events which might lead to aralar-1 re-activation in CDL is here given. Consistency of this account for CDL events further relies on the protective roles of PPARα and inhibition of mitochondrial and plasma membrane citrate transporters in non-CD HCC.

肝细胞癌（HCC）是临床实践和代谢研究中长期存在的问题。更好地了解 HCC 发病机制的新线索可能与 citrin（天冬氨酸-谷氨酸载体 1）缺乏症 (CD) 患者的代谢环境有关。由于 citrin-deficient 肝 (CDL) 易患 HCC，它代表了一种独特的代谢模型，突出了 HCC 促进机制，提供了与经典代谢综合征/肥胖/非酒精性脂肪肝病 (NAFLD)/ HCC 研究轴。反过来，HCC的代谢特征可以揭示CDL的发病机制。其中，HCC 诱导的 aralar-1（天冬氨酸-谷氨酸载体 2）的重新激活，生理上不在成人肝脏中表达，可能发生在 CDL 中，因此，CDL 将利用线粒体天冬氨酸 - 谷氨酸载体的基因冗余。这种提出的（aralar-1 再激活）和已知的（柠檬酸/苹果酸循环）适应性机制可以替代 CD 中受损的功能，并且与 CD 的临床缓解阶段和中链甘油三酯 (MCT) 的 CD 改善相一致。然而，这些代谢适应性益处也可以促进 HCC 的发展。在 CD 中，由于 PPARα 下调，肝脏线粒体脂肪酸衍生的乙酰辅酶 A 将与葡萄糖衍生的乙酰辅酶 A 一样，用于脂质合成代谢和燃料核乙酰化事件，这可能触发 aralar-1 再激活如在非 CD HCC 中所见。本文简要介绍了这些可能导致 CDL 中 aralar-1 重新激活的代谢事件。