Severity-dependent and sex-biased dysregulation of A-to-I RNA editing in COVID-19 reveals CTSS as a key regulatory target.

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.