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Ribosomal RNA-derived fragments in cancer: molecular identity, cellular context, and functional evidence

Year: 2026
Type: review
Abstract: Ribosomal RNA-derived fragments (rRFs), also termed rRNA-derived small RNAs (rsRNAs), occur in cells and biofluids, but their detection does not establish biological activity. This review systematically summarizes current research on rRF biogenesis, intracellular functions, extracellular localization and carriage, and clinical associations, while emphasizing that the detection of rRFs does not in itself establish biological function. Stress-associated cleavage, candidate-specific non-canonical processing, and extracellular ribosome fragmentation can each contribute to the observed repertoire. Functional cancer studies remain concentrated in a few candidates: depletion of a 28S-derived rRF3 affects H1299 cell phenotypes; rsRNA-28S inhibition increases PTGIS expression and taxane resistance in prostate-cancer cells; and synthetic gastric-cancer S2 and S7 mimics alter target reporters and protein abundance. These findings do not establish a common rRF pathway or therapeutic efficacy. Tissue and circulating signatures show diagnostic or prognostic associations, including a methylation-sensitive 28S fragment assay, but many cohorts are small and lack prospective external validation. Therapeutic development could test inhibition of a confirmed tumor-promoting fragment or replacement of a protective fragment, provided that endogenous function, selectivity over parental rRNA, delivery, and safety are established. Overall, rRFs show emerging biological and biomarker potential in cancer, but their clinical translation will require stronger mechanistic validation, prospective clinical evidence, and rigorous assessment of delivery and safety.
DOI: 10.3389/fcell.2026.1950076
Language: English
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223174082
FWCI:
Cites: 40
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Related to: 10