Mass spectrometry-based glycomics towards GlycoRNA
Published 01 April, 2026
Chemical modification of biomolecules is the foundation for dynamic regulation of biological systems. For decades, it was widely accepted that glycosylation predominantly modifies proteins and lipids. However, pioneering research has revealed that glycans can be metabolically integrated into RNA molecules, forming "glycoRNA". These glycoRNAs are ubiquitously distributed across various cell types and species, participating in essential biological processes such as immune modulation and intercellular communication. For instance, they have been shown to regulate migration during inflammatory responses and facilitate exosome uptake through interactions with Siglecs.
To further elucidate their biological functions, precise structural characterization is necessary. Mass spectrometry (MS), with its high sensitivity and capacity to resolve complex structural isomers, has become an indispensable tool in this emerging field. In a new review published in KeAi's Glycoscience & Therapy, a team of researchers examined the MS-based GlycoRNA analytical pipeline, covering critical phases from sample collection and RNA extraction to glycopeptide enrichment and final computational data interpretation.
The authors took into account the unique biochemical characteristics of RNA. An aspect highlighted was the systematic overview of glycoRNA enrichment strategies, including metabolic labeling approaches (Ac4GalNAz) and chemoenzymatic labeling methods (StCEL and rPAL), which enable the selective capture and enrichment of glycoRNA from complex biological samples. Furthermore, the authors discussed the integration of LC-MS/MS analysis with multiple ion dissociation techniques, such as CID, HCD, and ETD, together with bioinformatics tools for glycan identification and structural analysis, including GlycoNote and GlycanDIA Finder.
Overall, the review provides a systematic reference for MS-based RNA glycomics, summarizing analytical strategies to offer an integrated workflow for reliable identification and structural analysis of glycoRNA. By outlining these MS-based glycomic methodologies, it establishes a methodological framework for glycoRNA research and promotes further studies in this emerging field. In addition, MS-based glycoRNA profiling enables comprehensive characterization of glycobiological profiles, revealing distinctive patterns of glycan abundance across physiological and pathological states.
Notably, the aberrant expression of specific glycan motifs, particularly sialylated and fucosylated glycans, may serve as potential biomarkers for disease diagnosis and prognosis, highlighting the potential of glycoRNA research to advance biomedical research and precision medicine.
Contact author:
Haojie Lu and Yixuan Xie Department of Chemistry and Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
luhaojie@fudan.edu.cn (H. Lu); axexie@fudan.edu.cn (Y. Xie),
Funder:
This study is supported by the National Key R&D Program of China (2024YFA1306300 to H.L.)，the National Natural Science Foundation of China (22434001 to H.L. and 22507114 to Y.X.), and the Greater Bay Area Institute of Precision Medicine I0036(A) to Y.X.
Conflict of interest:
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Haojie Lu reports financial support was provided by National Key R&D Program of China. Haojie Lu reports financial support was provided by National Natural Science Foundation of China. Yixuan Xie reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.