Structural and mechanistic basis of ADAR1-mediated RNA editing and immune regulation

Adenosine deaminase acting on RNA 1 (ADAR1) is a central regulator of innate immunity. By binding to and catalyzing adenosine-to-inosine deamination within double-stranded RNAs, ADAR1 mitigates the immunogenicity of self-derived RNAs and preserves cellular homeostasis. In this review, we summarize recent structural and mechanistic advances that illuminate key features of ADAR1 architecture, including how its multi-domains engage dsRNA substrates and contribute to substrate selectivity. Integrated with decades of biochemical and genetic studies, these insights refine our understanding of ADAR1's catalytic mechanism, domain-specific activities, and roles in suppressing immune signaling. We further highlight emerging knowledge on ADAR1's RNA substrate landscape, its interactions with protein partners, and the mechanistic principles that underlie its broad RNA editing and immune regulatory functions, with implications for disease pathogenesis and therapeutic RNA editing.