中山大学鞠怀强课题组的一项最新研究探明了AHCY-腺苷复合体重新连接mRNA甲基化以增强脂肪酸的生物合成和肿瘤发生。2026年1月19日出版的《细胞研究》发表了这项成果。

该课题组人员在这里表明，腺苷高半胱氨酸酶(AHCY) -腺苷复合物以非全局方式增加mRNA m⁶A水平，促进脂肪酸合成和肿瘤发生。腺苷通过与蛋氨酸代谢酶AHCY结合形成复合物而不是依赖于腺苷受体，从而增加mRNA m⁶A水平。AHCY -腺苷复合物促进AHCY二聚化，腺苷对二聚体的稳定性至关重要。AHCY二聚体阻碍脂肪质量和肥胖相关蛋白（FTO）在Q86位点与含有VWDRACH基序的RNA结合，增加m⁶A水平，上调脂肪生成基因，特别是ACACA和SCD1，导致脂质代谢重编程。

相反，失去二聚体或FTO结合能力但保留水解酶活性的AHCY突变体可以抑制脂肪生成和肿瘤生长，而不会显著影响AHCY介导的蛋氨酸分解代谢。小鼠AHCY的缺失和肿瘤细胞和患者来源的异种移植模型中AHCY二聚体的破坏限制了肿瘤的生长。他们的发现证明了蛋氨酸代谢和mRNA m⁶A修饰之间的关键SAM无关的联系，影响去甲基化酶底物特异性。这种蛋氨酸循环和脂质代谢之间的新联系为抗癌治疗提供了新的策略。

据了解，蛋氨酸代谢产生底物S-腺苷蛋氨酸（SAM）， SAM调节表观遗传修饰，对各种细胞过程，特别是肿瘤发生至关重要。然而，蛋氨酸代谢是否涉及独立于SAM的表观遗传机制以及这些机制在肿瘤发生中起什么作用仍不清楚。

附：英文原文

Title: The AHCY–adenosine complex rewires mRNA methylation to enhance fatty acid biosynthesis and tumorigenesis

Author: Liao, Kun, Cao, Fen, Wei, Chen, Qian, Zheng-Yu, Hu, Hong-Rong, Pan, Wen-Feng, Feng, Zi-Qing, Lian, Sen-mao, Xiao, Zi-Xuan, Sheng, Hui, Mo, Hai-Yu, Zhao, Yi-Xuan, Wu, Qi-Nian, Zeng, Zhao-Lei, Li, Bo, Xu, Rui-Hua, Ju, Huai-Qiang

Issue&Volume: 2026-01-19

Abstract: Methionine metabolism generates the substrate S-adenosylmethionine (SAM), which regulates epigenetic modifications crucial for various cellular processes, particularly tumorigenesis. However, whether methionine metabolism involves epigenetic mechanisms independent of SAM and what roles such mechanisms play in tumorigenesis remain unclear. We show here that the adenosylhomocysteinase (AHCY)–adenosine complex increases mRNA m6A levels in a non-global manner, promoting fatty acid synthesis and tumorigenesis. Adenosine increases mRNA m6A levels by binding to the methionine metabolism enzyme AHCY to form a complex, rather than depending on adenosine receptors. The AHCY–adenosine complex facilitates AHCY dimerization, with adenosine being crucial for dimer stability. AHCY dimers hinder the binding of fat mass and obesity-associated protein (FTO) at the Q86 site to RNA containing the VWDRACH motif, increasing m6A levels and upregulating lipogenesis genes, especially ACACA and SCD1, thus leading to reprogramming of lipid metabolism. Conversely, AHCY mutants that have lost dimerization or FTO-binding ability but retain hydrolase activity suppress lipogenesis and tumor growth without significantly affecting methionine catabolism mediated by AHCY. Loss of AHCY in mice and disruption of AHCY dimerization in tumor cells and patient-derived xenograft models restricted tumor growth. Our findings demonstrate a key SAM-independent link between methionine metabolism and mRNA m6A modification that affects demethylase substrate specificity. This novel link between the methionine cycle and lipid metabolism suggests new strategies for anticancer therapy.

DOI: 10.1038/s41422-025-01213-5

Source: https://www.nature.com/articles/s41422-025-01213-5