糖脂代谢重塑是肝细胞癌HCC的基本特征，其协同调控HCC发生的核心机制尚待进一步阐明。线粒体醛脱氢酶ALDH6A1催化嘧啶和缬氨酸代谢中间产物甲基丙二酸半醛脱氢生成乙酰辅酶A、丙酰辅酶A与NADH，进入三羧酸循环和氧化磷酸化。前期公共数据库、组织芯片和新收肝癌样本的研究分析显示ALDH6A1表达在肝癌中显著下调；其表达水平与肝癌病理分级负相关，与病人预后正相关。ALDH6A1抑制肝癌细胞增殖、迁移和裸鼠体内皮下成瘤的能力。ALDH6A1显著影响线粒体功能，导致NADH和ROS增加，但耗氧率和线粒体膜势能降低。ALDH6A1降低肝癌细胞的乳酸水平，减少了脂质堆积。ALDH6A1还能与线粒体复合物I的组分NDUFS7以及三羧酸循环中的MDH2相互作用。这些前期研究提示ALDH6A1可能通过影响线粒体功能，从而调控糖脂代谢重塑、抑制HCC发生。我们计划采用Seahorse与代谢组质谱等技术系统分析ALDH6A1对糖酵解、TCA循环和氧化磷酸化的影响；利用代谢相关小鼠HCC模型，体内验证ALDH6A1在糖脂代谢重塑和HCC发生中的功能；RNA-Seq和代谢组整合解析ALDH6A1作用的机制和网络。本研究将进一步揭示代谢稳态失衡、糖脂代谢重塑在HCC发生发展中的核心作用，为研发HCC治疗新策略提供科学依据。

Metabolic rewiring of glucose and fat is one of hallmarks of hepatocellular carcinoma (HCC). However, the regulatory mechanism collaboratively promoting HCC remains to be further addressed. Mitochondria Aldehyde dehydrogenase family 6 member A1 (ALDH6A1) catalyzes dehydrogenation of methylmalonate semialdehyde, which is an intermediate product of pyrimidine and valine catabolism. Analysis of public database, tissue chip and freshly collected HCC patient samples showed that ALDH6A1 was downregulated in HCC. ALDH6A1 expression level was negatively correlated to pathological stage of HCC and positively correlated to prognosis of HCC patients. ALDH6A1 functioned to suppresse HCC proliferation, migration and the ability to form subcutaneous tumor in nude mice. ALDH6A1 also affected mitochondria function evidenced by increase of NADH and ROS production but reduction of oxygen consumption rate and mitochondria membrane potential. ALDH6A1 also decreased glucose 6-phosphate production as well as fat accumulation. It also interacted with NDUFS7 and MDH2, components of mitochondria complex I and tricarboxylic acid (TCA) cycle. These observations suggest that ALDH6A1may alter mitochondria function to regulate metabolic reprogramming of glucose and fat and promote HCC occurrence. We propose to dissect the effect of ALDH6A1 on glycolysis, TCA cycle and oxidative phosphorylation by using Seahorse and metabolomic mass spectrometry techniques; verify the in vivo function of ALDH6A1 in suppressing HCC by using HCC mouse models related to metabolism; unveil the regulatory network by integral analysis of RNA-Seq and targeted metabolome data. This study will further unveil the hardcore mechanism of the disturbed metabolic homeostasis and metabolic reprogramming of glucose and fat in HCC pathogenesis. It also provides new insights and evidence for the development of novel strategy for HCC therapy.