N6-methyladenosine-containing messenger RNA (m6A-mRNA) (m6A-mRNA)

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNA (mRNA), serving as a central regulator of the epitranscriptome (Source [1], [14]). This dynamic and reversible modification is orchestrated by 'writers' (e.g., METTL3, METTL14) that install the mark, 'erasers' (e.g., FTO, ALKBH5) that remove it, and 'readers' (e.g., YTHDF proteins, IGF2BPs) that recognize the modification to dictate mRNA processing (Source [1], [2]). The m6A modification influences nearly every stage of the RNA life cycle, including splicing, nuclear export, stability, and translation efficiency, thereby playing a fundamental role in cell fate decisions and stress responses (Source [5], [11]). Dysregulation of m6A-containing mRNA is a hallmark of many diseases, particularly aggressive cancers such as acute myeloid leukemia (AML) and various solid tumors, where it drives oncogenic signaling and therapeutic resistance (Source [17], [18], [22]). Consequently, the proteins regulating m6A mRNA levels have emerged as promising therapeutic targets, with several small-molecule inhibitors of METTL3 and FTO currently in clinical and preclinical development (Source [7], [15], [16]). Modulating this epitranscriptomic axis offers a novel approach to controlling gene expression in pathological states without altering the underlying DNA sequence.

Other names

m6A-modified mRNAN6-methyladenosine mRNARNA N6-methyladenosine modificationEpitranscriptomic m6A modification

Pharmacological agents targeting the m6A axis primarily function by inhibiting the enzymes responsible for its regulation, including 'writers' (methyltransferases), 'erasers' (demethylases), and 'readers' (recognition proteins). Inhibition of writers like METTL3 reduces the global or site-specific m6A modification of mRNA, while inhibition of erasers like FTO increases it. These changes alter the downstream fate of targeted transcripts, including their splicing patterns, nuclear export, half-life, and translation efficiency. Reader inhibitors block the physical interaction between the m6A mark and binding proteins, effectively preventing the cellular interpretation of the modification.