The Zα domain of ADAR1: emerging roles in cancer biology and evidence as a promising therapeutic target

Adenosine deaminase acting on RNA 1 (ADAR1) has emerged as an important cancer dependency and suppressor of innate immunity. While early therapeutic strategies focused on global enzymatic inhibition, these approaches may compromise essential homeostatic functions of the constitutively expressed ADAR1-p110 isoform. Growing evidence highlights editing-independent functions uniquely mediated by the interferon-inducible ADAR1-p150 isoform. Through its conformation-specific Zα domain, ADAR1-p150 binds Z-nucleic acids and suppresses MDA5-, PKR-, and ZBP1-driven innate immune activation, thereby promoting tumor immune evasion and adaptation to inflammatory stress. Consequently, selectively disrupting this p150-mediated suppression may represent a more therapeutically tractable strategy than global ADAR1 inhibition, with the Zα domain providing a potentially selective mechanistic interface. This review synthesizes current understanding of Zα-mediated immune regulation, evaluates emerging domain-specific therapeutic approaches, and provides a comprehensive guide to the biophysical and cell-based assays used to interrogate Zα interactions, highlighting key mechanistic gaps that may inform future p150-selective translational interventions.