ArticleRNA biology2026
Severity-dependent and sex-biased dysregulation of A-to-I RNA editing in COVID-19 reveals CTSS as a key regulatory target.
Article in RNA biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
SARS-CoV-2 infection causes diverse clinical outcomes, with men facing higher risks of severe disease. Adenosine-to-inosine (A-to-I) RNA editing mediated by ADAR enzymes governs innate antiviral immunity, yet its contribution to COVID-19 severity and sex-biased disease remains unclear. We performed epitranscriptomic profiling on 126 blood samples from non-COVID controls and COVID-19 patients spanning different disease severities. We detected 1,466 differentially RNA-edited sites in 514 genes linked to clinical outcomes. Although ADAR expression increased in COVID-19 patients overall, it was strongly reduced in ICU patients compared with non-ICU patients, and this shift was far more prominent in males. This severity-associated and sex-biased ADAR/ADARB1 downregulation coincided with decreased global RNA editing and perturbed expression of immune-related edited transcripts. Cathepsin S (CTSS) was identified as a central regulatory node: elevated A-to-I editing within its 3' UTR in ICU patients stabilizes CTSS mRNA. Without stratifying by disease severity, ADAR expression and global editing showed no significant sex differences; the large sex divergence only appeared among ICU patients. This indicates severity-dependent, not infection-innate, disruption of A-to-I editing, disproportionately amplified in critically ill males. CTSS 3'UTR editing may serve as a biomarker for patient stratification, revealing a mechanistic connection between epitranscriptomic changes and male-biased severe COVID-19.
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