RNA modification systems as therapeutic targets

Linda Zhang; Jiangbo Wei; Zhongyu Zou; Chuan He

doi:10.1038/s41573-025-01280-8

RNA modification systems as therapeutic targets

Nat Rev Drug Discov. 2025 Sep 17. doi: 10.1038/s41573-025-01280-8. Online ahead of print.

Authors

Linda Zhang^{1

2}, Jiangbo Wei^{1

2}, Zhongyu Zou^{1

2}, Chuan He^{3

4}

Affiliations

¹ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA.
² Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA.
³ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
⁴ Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.

PMID: 40962853
DOI: 10.1038/s41573-025-01280-8

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.

Publication types

Review