Editome profiling and cross-cohort validation reveal A-to-I RNA editing dysregulation in the hippocampus and prefrontal cortex of sepsis patients

Introduction Sepsis is a severe systemic inflammatory response to infection, potentially resulting in serious neurological complications. Adenosine-to-inosine (A-to-I) RNA editing is a critical epitranscriptomic process, yet its clinical involvement in different brain regions during sepsis remains to be elucidated. Methods We conducted a comprehensive editome analysis and experimental validation to characterize A-to-I RNA editing in hippocampal and prefrontal cortical tissues from a sepsis cohort, as well as in brain tissues from a validation cohort. Results Our findings revealed diverse dysregulation of RNA editing in these brain regions, with a substantial reduction in average RNA editing levels in the hippocampus but not in the prefrontal cortex. Moreover, cross-cohort and cross-tissue analysis identified eight key genes with dysregulated RNA editing during sepsis, particularly mitochondrial antiviral-signaling protein ( MAVS ), whose RNA editing was significantly downregulated. ADAR knockout or knockdown in multiple cell lines reduced both MAVS RNA editing and expression, confirming MAVS as a target of ADAR-mediated A-to-I RNA editing. Moreover, human vascular endothelial cells stimulated with LPS for 2 hours exhibited downregulated MAVS RNA editing, consistent with findings in sepsis patients, as well as reduced ADAR and MAVS expression, suggesting a potential role for ADAR-mediated RNA editing in regulating MAVS expression during inflammation. Consistently, ADAR and MAVS expression showed a positive correlation in both brain regions (Spearman’s ρ > 0.49, P < 1 × 10 -7 ). Discussion Our results thus provide new insight into the importance of the clinical epitranscriptomic landscape in different brain regions during sepsis and warrant further investigation into therapeutic strategies to mitigate cognitive impairment in sepsis.