在富含葡萄糖条件下，碳水化合物应答元件结合蛋白（ChoRE）结合蛋白（ChREBP）及其结合伴侣Max样蛋白X（MLX）介导了脂肪合成基因的转录。葡萄糖和脂质代谢的失调经常发生在癌症中，包括肝细胞癌（HCC）。然而，目前尚不清楚葡萄糖诱导的脂质合成程序是否在HCC发展中起作用。在这里，我们展示了MLX表达在HCC标本中升高，而MLX表达的下调抑制了HCC细胞的增殖。在小鼠中，肝特异性的Mlx敲除导致脂质合成基因表达和循环中脂质水平的显著下降。有趣的是，在没有Mlx的情况下，多种HCC模型（如二硝基胺（DEN）处理和肿瘤基因的水力注射（AKT / RAS或CTNNB1 / RAS））的肿瘤发展被强烈阻断。然而，高脂饮食可以在Mlx缺陷肝脏中部分恢复肿瘤发生，表明脂质合成在HCC发展中起关键作用。此外，通过腺相关病毒实现肝特异性表达一个显性负性MLX（dnMLX）有效地阻断了小鼠的肿瘤发生。因此，葡萄糖诱导的脂质合成程序在HCC的发展中是必需的，并且ChREBP：MLX转录因子可以作为癌症治疗的潜在靶点。© 2023年，作者，独家授权于Springer Nature Limited。

The Carbohydrate Response Element (ChoRE) Binding Protein (ChREBP) and its binding partner Max-like protein X (MLX) mediate transcription of lipogenic genes under glucose-rich conditions. Dysregulation of glucose and lipid metabolism frequently occurs in cancers, including Hepatocellular Carcinomas (HCCs). However, it is currently unclear whether the glucose-induced lipogenic program plays a role in the development of HCCs. Here, we show that MLX expression is elevated in HCC specimens and downregulation of MLX expression inhibits proliferation of HCC cells. In mice, liver-specific knockout of Mlx results in dramatic decrease in the expression of lipogenic genes and lipid levels in circulation. Interestingly, in the absence of Mlx, the development of tumors in multiple HCC models, such as diethylnitrosamine (DEN) treatment and hydrodynamic injection of oncogenes (AKT/RAS or CTNNB1/RAS), is robustly blocked. However, a high-fat diet can partially restore tumorigenesis in Mlx-deficient livers, indicating a critical role of lipid synthesis in HCC development. In addition, liver-specific expression of a dominant negative MLX (dnMLX) via adeno-associated virus effectively blocks tumorigenesis in mice. Thus, the glucose-induced lipogenic program is required in the development of HCC, and the ChREBP: MLX transcription factors serve as a potential target for cancer therapies.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.