N6-methyladenosine (m6A), the most prevalent internal RNA modification in eukaryotic cells, is a dynamic regulator of RNA metabolism and cancer biology. In colorectal cancer (CRC), dysregulated m6A reshapes transcriptomic programs that control tumor growth, metastasis, immune evasion, and therapeutic resistance. However, the context-dependent functions of individual m6A regulators remain incompletely defined, the integration of m6A with canonical oncogenic signaling remains incomplete, and its role in metabolic reprogramming lacks a systematic overview. This review aims to integrate current evidence on m6A regulatory machinery in CRC, clarify its coordination with oncogenic signaling and metabolic pathways, and highlight emerging translational implications. The key players regulating m6A in CRC progression are m6A “writers”, including methyltransferase-like 3 and methyltransferase-like 14; m6A “erasers”, including fat mass and obesity-associated protein and AlkB homolog 5; and m6A “readers”, including the YTH m6A RNA-binding protein family and the insulin-like growth factor 2 mRNA-binding protein family. m6A modification coordinates key oncogenic pathways, including Wnt/β-catenin, PI3K/Akt, MAPK, and p53 signaling. Moreover, m6A-dependent regulation of metabolic enzymes such as hexokinase 2, pyruvate kinase M2, and fatty acid synthase promotes the reprogramming of glucose, amino acid, and lipid metabolism, linking epitranscriptomic control to bioenergetic adaptation. We also discuss context-dependent and paradoxical functions of m6A regulators and advances in m6A-targeted therapies. In conclusion, m6A modification functions as a central regulatory hub in CRC by integrating signaling networks and metabolic pathways. Deeper mechanistic insights into spatiotemporal m6A regulation may accelerate the development of biomarkers and targeted therapies for precision CRC management.
Sheng et al. (Sun,) studied this question.