Abstract
Ribonucleotide bases can be chemically modified by cellular enzymes such as methyltransferases to regulate RNA metabolism and biological processes. The association between abnormal levels of RNA modification effector proteins and human diseases has spurred interest in therapeutic targeting of RNA modification systems, and an agent that inhibits the RNA-methylating enzyme METTL3 has entered clinical trials. Despite the promise of these pathways, therapeutic agents targeting proteins that write, read and erase RNA modifications are still limited. In this Review, we describe the cellular functions and disease associations of proteins that regulate RNA modifications. We focus on the N6-methyladenosine pathway, highlighting early-stage advances in inhibitor development such as against the YTH reader proteins, but we also discuss the potential of targeting other RNA modification pathways. Targeting RNA modification systems offers a new strategy for treating cancer, improving immunotherapy and enhancing stem cell therapies.
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The authors are grateful for support from National Institutes of Health (NIH) Grant RM1 HG008935 (C.H.).
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C.H. is a scientific founder, a member of the scientific advisory board and equity holder of Aferna Bio, Inc. and Ellis Bio Inc.; a scientific cofounder and equity holder of Accent Therapeutics, Inc.; and a member of the scientific advisory board of Rona Therapeutics. L.Z., J.W. and Z.Z. declare no competing interests.
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Zhang, L., Wei, J., Zou, Z. et al. RNA modification systems as therapeutic targets. Nat Rev Drug Discov (2025). https://doi.org/10.1038/s41573-025-01280-8
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DOI: https://doi.org/10.1038/s41573-025-01280-8
