Emerging roles of RNA editing in cellular function and therapeutics

RNA editing comprises of post-transcriptional modification that proposes site-specific nucleotide changes into RNA molecules, increasing transcriptomic and proteomic diversity well beyond the information encoded within the genome. The two principal biochemical mechanisms; adenosine-to-inosine (A-to-I) editing catalyzed by the adenosine deaminase acting on RNA (ADAR) family, and cytidine-to-uridine (C-to-U) editing mediated by the apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family together control a broad spectrum of physiological and pathological procedures. The objective of this review is to combine present evidence on the multifaceted roles of RNA editing across cellular contexts and to critically assess its translational potential within the therapeutic landscape. ADAR1 safeguards cellular homeostasis by avoiding irregular activation of the innate immune sensors MDA5 and PKR by endogenous double-stranded RNA (dsRNA), while de-regulation of ADAR-mediated editing has been implicated in tumorigenesis, viral pathogenesis, and neurological dysfunction. C-to-U editors of the AID/APOBEC family are majorly involved in innate and adaptive immunity, contributing to antibody diversification and antiviral restriction, and linked with cancer progression and neurological disease. On the therapeutic front, programmable A-to-I RNA editing platforms which include LEAPER, RESTORE, and antisense oligonucleotide-based approaches have emerged as powerful tools for rectifying disease-causing mutations at the transcript level, offering reversible and transient pharmacodynamic effects that avoid the permanence and heritability risks linked with genomic interventions. Some oligonucleotide-based RNA editing therapeutics are currently advancing through clinical trials, with Wave Life Sciences' WVE-006 representing an example of first-in-human ADAR-based programmable editing. Nevertheless, critical limitations persist off-target transcriptome-wide editing events, differential ADAR isoform expression across tissues, and the immunogenic risks linked with long-term interference with endogenous ADAR activity remain unresolved challenges that require both mechanistic understanding and clinical translation. Together, this review underscores RNA editing as an essential layer of epitranscriptomic regulation and positions programmable editing platforms as a compelling, yet still maturing, in precision medicine.