A moonlighting function: the methionine cycle rewires RNA methylation

www.nature.com/cr www.cell-research.com Cell Research RESEARCH HIGHLIGHT A moonlighting function: the methionine cycle rewires RNA methylation Zhaoxu Xu1,2,3 and Jianjun Chen 1,2,3 ✉ © The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences 2026 1234567890();,: Cell Research (2026) 0:1–2; https://doi.org/10.1038/s41422-026-01231-x Methionine metabolism is classically viewed as an epigenetic supply line that fuels the methylation of histones, DNA, and RNA via the universal methyl donor S-adenosylmethionine (SAM). In a recent Cell Research study, Liao et al. uncover a SAM-independent mechanism in which the methionine-cycle enzyme adenosylhomocysteinase (AHCY) moonlights as a metabolite-gated scaffold, rewiring mRNA N6-methyladenosine (m6A) regulation by tuning the activity of the RNA demethylase FTO. Epigenetic deregulation is a hallmark of cancer initiation and progression.1 While DNA and histone methylation shape chromatin architecture, RNA methylation adds a reversible layer of posttranscriptional regulation. Among more than 170 known RNA modifications, m6A is the most abundant internal modification in eukaryotic RNAs. It is primarily deposited by the METTL3–METTL14 “writer” complex and removed by the “erasers” FTO and ALKBH5, thereby fine-tuning mRNA splicing, stability, and translation2 (Fig. 1a). Dysregulation of m6A modification has been widely implicated in the progression of various cancers.3 Emerging evidence further indicates that m6A methylation is influenced not only by “writer,” “eraser,” and “reader” proteins, but also by cellular metabolic states — particularly the availability of SAM and related metabolites.4,5 SAM is synthesized from dietary methionine by methionine adenosyltransferases (MATs). Methyl transfer reactions convert SAM to S-adenosylhomocysteine (SAH), a potent allosteric inhibitor of methyltransferases (e.g., METTL3). The methionine-cycle enzyme AHCY hydrolyzes SAH into homocysteine and adenosine (ADO), thereby maintaining cellular methylation capacity (Fig. 1a). Accordingly, the SAM/SAH ratio has long been considered a key determinant of methyltransferase activity.1,4 Consistent with this view, dietary methionine restriction lowers SAM levels and reduces global m6A levels, thereby inhibiting tumor growth and enhancing anti-tumor immunity in vivo, motivating therapeutic interest in targeting methionine metabolism.6 However, Liao et al.7 found that although SAM supplementation rescues histone methylation defects caused by methionine deficiency, it fails to fully restore mRNA m6A levels, implying that methionine metabolism may also regulate RNA methylation through SAM-independent pathways. Whether such SAM-independent regulation of m⁶A exists, and how it might contribute to cancer, remained unclear. In their study,7 Liao et al. uncover a novel, non-classical pathway by which methionine metabolism regulates RNA methylation. They show that AHCY modulates m6A methylation through allosteric dimerization and selective inhibition of FTO, thereby driving fatty acid biosynthesis and tumorigenesis. Using a CRISPR–Cas9-based screen of metabolic enzymes, the authors identify AHCY as a key positive regulator of m6A methylation; its depletion markedly reduces m6A levels even under SAM-sufficient conditions. AHCY is highly conserved and exists in monomeric, dimeric, and tetrameric states, with the tetramer exhibiting the highest hydrolase activity.8 Consistent with prior studies showing that AHCY inhibition disrupts the methionine cycle, lowers SAM levels, and reduces tumor burden in Apc-deficient intestinal tumor models9 —an effect corroborated by AHCY-knockout mice generated by Liao et al.7 — the decrease in m6A levels caused by AHCY loss could not be fully rescued by SAM supplementation or by adjusting the SAM/SAH ratio. These results indicate that AHCY regulates mRNA m6A methylation through a SAM-independent mechanism. Mechanistically, ADO directly binds AHCY, inducing a conformational change that favors the formation of an enzymatically inactive dimer. This dimer acts as a “molecular wedge” by inserting into the RNA-binding surface of the demethylase FTO and restricting FTO binding to specific sequence contexts on target mRNAs (e.g., VWDRACH, where V = G/A/C and W = A/U). As a result, FTOmediated demethylation of transcripts encoding fatty acid biosynthetic enzymes, such as ACACA and SCD1, is selectively inhibited, leading to increased m6A methylation, elevated transcript abundance, enhanced de novo fatty acid synthesis, higher monounsaturated fatty acid levels, and accelerated tumor growth (Fig. 1b). Compelling genetic support comes from separation-of-function AHCY mutants that retain hydrolase activity but lose dimerization or FTO-binding capacity, demonstrating that AHCY’s non-enzymatic scaffolding function rewires RNA methylation, drives the reprogramming of lipid metabolism, and promotes tumorigenesis. Importantly, TCGA analyses associate AHCY expression with poor prognosis across multiple cancer types, including colorectal cancer. Conditional deletion of Ahcy in the intestinal epithelium reduced tumor burden in an azoxymethane/dextran sulfate sodium colorectal cancer model, accompanied by decreased ACC1 expression and reduced proliferation markers.7,9 In orthotopic colorectal organoid tumors, FTO loss partially reversed the metabolic changes and tumor-suppressive effects of Ahcy deletion, providing genetic evidence for an AHCY–FTO axis in tumorigenesis. Notably, a peptide designed to disrupt the AHCY dimerization interface weakened the AHCY–FTO interaction, reduced m6A levels on lipogenic transcripts, decreased lipid droplet accumulation, and suppressed tumor growth, highlighting the therapeutic potential of targeting this pathway (Fig. 1b). 1 Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA. 2Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA. 3Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA. ✉email: Z. Xu and J. Chen 2 Fig. 1 Canonical SAM-dependent methylation maintenance mechanisms and a moonlighting AHCY–ADO axis that rewires m6A regulation and lipid metabolism and promotes tumorigenesis. a The methionine cycle generates SAM, the universal methyl donor for cellular methylation reactions. Methionine is converted to SAM by methionine adenosyltransferases, such as MAT2A. SAM depletion triggers a negative feedback loop in which m6A-dependent stabilization of MAT2A mRNA restores SAM homeostasis. In parallel, m6A “writers” use SAM to modify mRNA, producing SAH, whereas “erasers” remove m6A and “readers” interpret this modification to shape mRNA fate. b The methionine cycle reprograms RNA methylation via a moonlighting mechanism. The AHCY–ADO complex drives AHCY dimerization, inhibits FTO activity, increases mRNA m6A leve (...truncated)