eIF3f promotes tumour malignancy by remodelling fatty acid biosynthesis in hepatocellular carcinoma

作者：Suiqing Zhou, Liren Zhang, Yue You, Kai Yu, Xiaofeng Tie, Yun Gao, Yining Chen, Feifan Yao, Ruizhi Zhang, Xiaopei Hao, Chunyao Fang, Xiangdong Li, Qing Li, Xuehao Wang · 发表于：Journal of Hepatology · 年份：2025 · DOI：10.1016/j.jhep.2025.02.045 · 被引用次数：30 · 研究领域：Cancer, Lipids, and Metabolism、Ferroptosis and cancer prognosis、Cancer, Hypoxia, and Metabolism

Background & Aims Fatty acid metabolism is closely associated with hepatocellular carcinoma (HCC). Elucidating the molecules that influence fatty acid metabolism in HCC is important for developing precision therapies. However, uncovering the precise molecular mechanisms underlying changes in fatty acid metabolism in tumour cells is challenging. In this study, we aimed to determine the characteristics of fatty acid metabolism in HCC. Methods We employed organoid models, single-cell RNA sequencing, and spatial transcriptomics to identify key genes involved in tumour fatty acid metabolism. Metabolomics, proteomics, metabolic flux analysis, and transmission electron microscopy were utilized to evaluate this metabolic process. Tumour malignancy was characterized using multi-species models. Changes in the immune microenvironment were analysed by time-of-flight mass cytometry and multiplexed immunohistochemistry. Gene knockdown targeting the liver was achieved using lipid nanoparticles. Results Eukaryotic translation initiation factor 3 subunit f (eIF3f) is upregulated in HCC tissues and is associated with poor prognosis. eIF3f directly interacted with and stabilised long chain acyl CoA synthetase 4 (ACSL4) through K48-linked deubiquitination, promoting fatty acid biosynthesis and malignancy. The increased fatty acid levels in the tumour microenvironment indirectly reduced CD8 + T-cell infiltration. In addition, phosphorylated eIF3f enhanced the interaction between eIF3f and ACSL4. ...