The methyltransferase-like proteins as core regulators of nucleic acid modifications and post-translation modification of proteins in disease pathogenesis and therapeutic implications.

The methyltransferase-like (METTL) family members are the central ‘writers’ of epitranscriptome modifications, catalyzing N6-methyladenosine (m6A), N7-methylguanosine (m7G), 3-methylcytosine (m3C) and other chemical markers that modify DNA, RNA, and proteins (both histones and non-histone proteins) to dynamically regulate gene expression. The METTL family is distinguished by structural diversity, substrate specificity and multifaceted roles in epigenetic regulation. Dysregulation of METTL proteins has been demonstrated to disrupt RNA stability, translational efficiency and signaling pathways, which has been associated with tumorigenesis, neurodegeneration and immune dysfunction. At present, there are still limitations in the knowledge of the cooperative networks among METTL members and with other major signaling pathways. The objective of the present study is to elucidate the regulatory mechanisms mediated by METTL across different levels, laying the groundwork for subsequent development of precision therapies targeting phenotypic enzyme modifications. This review comprehensively delineates the structural characteristics and molecular functions of METTLs, their cooperative interactions, and their pathophysiological regulatory networks organized by signaling pathways rather than disease categories. We evaluate their diagnostic potential as biomarkers and their therapeutic implications, with particular focus on emerging METTL inhibitors that have entered clinical trials. By systematically exploring the mechanisms behind their context-dependent functions and analyzing their potential for clinical translation, we provide a foundation for precision therapies targeting these core regulators of nucleic acid and protein methylation.