Cross-Cohort Evidence of Editome Dysregulation and Cell Growth-Related IGFBP7 Recoding Driven by ADARB1 in Fuchs Endothelial Corneal Dystrophy

Purpose: Fuchs endothelial corneal dystrophy (FECD) is a degenerative disease characterized by progressive loss of corneal endothelial cells, yet the role of adenosine-to-inosine (A-to-I) RNA editing mediated by adenosine deaminases acting on RNA (ADARs) remains unelucidated. Our current study aimed to investigate the A-to-I editome in FECD and its underlying epigenetic mechanisms. Methods: Cross-cohort editome analysis was performed using corneal endothelial transcriptome datasets from two independent FECD cohorts. RNA editing was identified and compared across groups to assess differential RNA editing and its associated gene functions and pathways, followed by cell experiments and RNA-sequencing (RNA-seq) to evaluate the functional impact of selected RNA editing events. Results: Our results showed a cross-cohort reduction of average A-to-I RNA editing levels and significant upregulation of ADARB1, with 10,416 differential RNA editing events in 1138 genes in FECD compared with controls, including FECD-related genes, such as transcription factor 4. Moreover, differentially edited genes were mainly involved in cell growth and autophagy-related pathways. Notably, FECD exhibited upregulated missense RNA editing, leading to K95R recoding in insulin-like growth factor binding protein 7 (IGFBP7), positively correlated with ADARB1 expression. In vitro overexpression of ADARB1 enhanced IGFBP7 K95R editing, inhibiting cell proliferation, and inducing apoptosis via the p53-p21 axis. Transcriptome analysis further revealed that cells overexpressing recoded K95R IGFBP7 exhibited compromised expression in the mitochondrial electron transport chain. Conclusions: Our findings demonstrate substantial editome dysregulation in FECD, highlighting a role of ADARB1-mediated IGFBP7 recoding in promoting cell apoptosis and dysfunction, and providing insights into the epigenetic mechanisms underlying FECD and potential therapeutic targets.