利用负责肝癌发生的关键调控因子对预防和治疗肝细胞癌（HCC）非常重要。然而，对于肝癌发生的关键参与因子仍知之甚少。我们研究了HCC的发生和进展的分子机制，以开发潜在的新治疗靶点。我们利用癌症基因组图谱-肝肝细胞癌（TCGA-LIHC）和基因型组织表达（GTEx）数据库来识别与HCC进展相关联的在肝脏中表达增强的基因。我们生成了小鼠肝特异性Ftcd基因敲除（Ftcd-LKO）模型，以研究HCC中甲酰亲和转移酶环化脱氨酶（FTCD）的作用。我们运用转录组学、代谢组学和蛋白组学数据的多组学分析，进一步分析FTCD表达对肝癌发生的分子影响。我们进行了功能和生物化学研究，以确定FTCD表达丧失的重要性和Akt抑制剂在FTCD缺失癌细胞中的治疗潜力。FTCD在肝脏中高度表达，但在HCC中显著下调。具有低FTCD水平的HCC患者预后较差，而肝硬化患者和低FTCD水平则明显更容易发展成HCC。肝细胞特异性FTCD基因敲除促进了鼠模型中较长时间二乙硝胺引起的慢性肝癌和自发性肝癌的发生。多组学分析显示，FTCD丧失影响了肝癌的脂肪酸和胆固醇代谢。机制上，FTCD丧失通过调节PTEN/Akt/mTOR信号通路上调了过氧化物酶体增殖物活化受体（PPAR）γ和甾体调控元件结合蛋白2（SREBP2），导致脂质积累和肝癌发生。综上所述，我们发现FTCD通过调控PPARγ和SREBP2信号通路在肝癌发生中调控脂质代谢机制，为通过下调FTCD治疗HCC提供了合理依据。利用负责肝癌发生的关键分子对预防和治疗HCC非常重要。本文鉴定了甲酰亲和转移酶环化脱氨酶（FTCD）作为最高表达的基因，可作为HCC患者的预测和预后标志物。我们构建并表征了第一个Ftcd肝特异性敲除小鼠模型。我们发现FTCD表达丧失通过调节PTEN/Akt/mTOR信号通路上调了过氧化物酶体增殖物活化受体（PPAR）γ和甾体调控元件结合蛋白2（SREBP2），导致脂质积累和肝癌发生，并为通过下调FTCD治疗HCC提供了合理依据。© 2023 作者

Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets.The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells.FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis.Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD.Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.© 2023 The Author(s).