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Review
. 2025 Sep;26(9):691-705.
doi: 10.1038/s41580-025-00852-1. Epub 2025 May 20.

Functions and therapeutic applications of pseudouridylation

Nan Luo #  1 , Qiang Huang #  1 , Meiling Zhang #  1   2 , Chengqi Yi  3   4   5   6
Affiliations
Review

Functions and therapeutic applications of pseudouridylation

Nan Luo et al. Nat Rev Mol Cell Biol. 2025 Sep.

Abstract

The success of using pseudouridine (Ψ) and its methylation derivative in mRNA vaccines against SARS-CoV-2 has sparked a renewed interest in this RNA modification, known as the 'fifth nucleotide' of RNA. In this Review, we discuss the emerging functions of pseudouridylation in gene regulation, focusing on how pseudouridine in mRNA, tRNA and ribosomal RNA (rRNA) regulates translation. We also discuss the effects of pseudouridylation on RNA secondary structure, pre-mRNA splicing, and in vitro mRNA stability. In addition to nuclear-genome-encoded RNAs, pseudouridine is also present in mitochondria-encoded rRNA, mRNA and tRNA, where it has different distributions and functions compared with their nuclear counterparts. We then discuss the therapeutic potential of programmable pseudouridylation and mRNA vaccine optimization through pseudouridylation. Lastly, we briefly describe the latest quantitative pseudouridine detection methods. We posit that pseudouridine is a highly promising modification that merits further epitranscriptomics investigation and therapeutic application.

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Conflict of interest statement

Competing interests: The authors have filed several patents for the RESTART technology.

References

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