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Peer-reviewedCC BYRNA biology

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

  • Jing-Yuan Wang1,2,3
  • Ya-Di Zhao1,2,3
  • Li-Ping Wang1,2,3
  • Yu-Qing Ren1,2,3
  • Jia-Nuo Li1,2,3
  • Teng Wang1,2,3
  • Hua-Kang Zhang1,2,3
  • Feng Zhu1,4
  • Jian-Huan Chen1,2,3
  • Yun-Yun Jin1,2,3,5
5 affiliations
  1. 1Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Department of Respiratory and Critical Care Medicine, Affiliated Wuxi Fifth Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China.
  2. 2Joint Primate Research Center for Chronic Diseases, Institute of Zoology of Guangdong Academy of Sciences, Jiangnan University, Wuxi, Jiangsu, China.
  3. 3MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
  4. 4Department of Respiratory and Critical Care Medicine, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, Jiangsu, China.
  5. 5School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.
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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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Cite

BibTeXRIS
BibTeX
@article{wang2026severitydependent,
  title = {{Severity-dependent and sex-biased dysregulation of A-to-I RNA editing in COVID-19 reveals CTSS as a key regulatory target.}},
  author = {Jing-Yuan Wang and Ya-Di Zhao and Li-Ping Wang and Yu-Qing Ren and Jia-Nuo Li and Teng Wang and Hua-Kang Zhang and Feng Zhu and Jian-Huan Chen and Yun-Yun Jin},
  journal = {RNA biology},
  year = {2026},
  month = oct,
  doi = {10.1080/15476286.2026.2736869},
  url = {https://europepmc.org/article/MED/42872762},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Severity-dependent and sex-biased dysregulation of A-to-I RNA editing in COVID-19 reveals CTSS as a key regulatory target.
AU  - Jing-Yuan Wang
AU  - Ya-Di Zhao
AU  - Li-Ping Wang
AU  - Yu-Qing Ren
AU  - Jia-Nuo Li
AU  - Teng Wang
AU  - Hua-Kang Zhang
AU  - Feng Zhu
AU  - Jian-Huan Chen
AU  - Yun-Yun Jin
PY  - 2026
DA  - 2026/10/14
JO  - RNA biology
DO  - 10.1080/15476286.2026.2736869
UR  - https://europepmc.org/article/MED/42872762
AB  - 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.
SN  - 1547-6286
SN  - 1555-8584
ER  -