FASN promotes lipid metabolism and progression in colorectal cancer via the SP1/PLA2G4B axis.

IF 7 2区生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2025-03-28 DOI:10.1038/s41420-025-02409-9

Xin Liu, Jiachun Lu, Xiangyu Ni, Yuxin He, Jiayu Wang, Zilin Deng, Guangbo Zhang, Tongguo Shi, Weichang Chen

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Abstract

Abnormal metabolic reprogramming is essential for tumorigenesis, metastasis, and the regulation of immune responses. Fatty acid synthase (FASN), a key enzyme in lipid metabolism, plays a crucial role in these processes. However, the relationship between FASN-mediated lipid reprogramming and the immune response in colorectal cancer (CRC) remains unclear. The present study demonstrated that FASN expression is elevated in CRC tissues and is significantly associated with poor prognosis. Functional experiments revealed that FASN promotes proliferation, migration, invasion, and phosphatidylcholine (PC) production in CRC cells. Additionally, in vivo experiments revealed that FASN knockdown significantly inhibits tumor growth and the spread of CRC cells to the lungs. Mechanistically, FASN, which is upregulated in CRC tissues, drives cancer cell proliferation, metastasis, and PC metabolism through the SP1/PLA2G4B axis, subsequently suppressing the antitumor response of natural killer (NK) cells in a PC-dependent manner. These findings provide new insights into lipid metabolism and the immunobiology of CRC, suggesting potential targets for the treatment and prevention of CRC. Schematic diagram showing the mechanism by which FASN promotes cancer cell proliferation, metastasis, and PC metabolism in CRC via the SP1/PLA2G4B axis, subsequently suppressing the antitumor response of NK cells in a PC-dependent manner. FFA free fatty acid, LPA lysophosphatidic acid, PA phosphatidate, DAG diglyceride, PC phosphatidylcholine, LPC lysophosphatidylcholine, CE cholesterol ester, TAG triacylglycerol.

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FASN通过SP1/PLA2G4B轴促进结直肠癌的脂质代谢和进展。

异常的代谢重编程对于肿瘤的发生、转移和免疫反应的调节是必不可少的。脂肪酸合成酶（FASN）是脂质代谢的关键酶，在这些过程中起着至关重要的作用。然而，fasn介导的脂质重编程与结直肠癌（CRC）免疫应答之间的关系尚不清楚。本研究表明，FASN在结直肠癌组织中表达升高，且与预后不良显著相关。功能实验显示，FASN促进结直肠癌细胞的增殖、迁移、侵袭和磷脂酰胆碱（PC）的产生。此外，体内实验显示，FASN基因敲低可显著抑制肿瘤生长和CRC细胞向肺部的扩散。机制上，FASN在结直肠癌组织中上调，通过SP1/PLA2G4B轴驱动癌细胞增殖、转移和PC代谢，随后以PC依赖的方式抑制自然杀伤（NK）细胞的抗肿瘤反应。这些发现为CRC的脂质代谢和免疫生物学提供了新的见解，为CRC的治疗和预防提供了潜在的靶点。FASN通过SP1/PLA2G4B轴促进CRC中癌细胞增殖、转移和PC代谢的机制示意图，随后以PC依赖的方式抑制NK细胞的抗肿瘤反应。游离脂肪酸、LPA溶血磷脂酸、PA磷脂酸、DAG二甘油酯、PC磷脂酰胆碱、LPC溶血磷脂酰胆碱、CE胆固醇酯、TAG三酰基甘油。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.