Volume 36, No 2, Feb 2026

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 36 Issue 2, February 2026: 152-172   |  Open Access

ORIGINAL ARTICLES

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

Kun Liao^1,† , Fen Cao^2,† , Chen Wei^1,† , Zheng-Yu Qian^1,† , Hong-Rong Hu³ , Wen-Feng Pan³ , Zi-Qing Feng¹ , Sen-mao Lian¹ , Zi-Xuan Xiao¹ , Hui Sheng¹ , Hai-Yu Mo¹ , Yi-Xuan Zhao⁴ , Qi-Nian Wu¹ , Zhao-Lei Zeng^1,5 , Bo Li^2,4,6,* , Rui-Hua Xu^1,5,7,* , Huai-Qiang Ju^1,5,*

¹State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
²Department of Urology, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, Guangdong, China
³Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
⁴Department of Biochemistry and Molecular Biology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
⁵Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China
⁶Experimental Education and Administration Center, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
⁷Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China
^†These authors contributed equally: Kun Liao, Fen Cao, Chen Wei, Zheng-Yu Qian
Correspondence: Bo Li(libo47@smu.edu.cn)Rui-Hua Xu(xurh@sysucc.org.cn)Huai-Qiang Ju(juhq@sysucc.org.cn)

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.

https://doi.org/10.1038/s41422-025-01213-5

FULL TEXT | PDF

Browse 82