Abstract
Adenosine deaminase acting on RNA 1 (ADAR1) regulates mRNA fate and function through adenosine-to-inosine (A-to-I) RNA editing and RNA-binding activities. While its role in innate immunity is established, the broader regulatory functions of ADAR1 in macrophages remain poorly defined. Here, we systematically profiled ADAR1 expression across human immune cells and identified marked enrichment in macrophages, driven by selective usage of an alternative transcription start site during monocyte-to-macrophage differentiation. ADAR1 binds, edits, and modulates key macrophage targets involved in efferocytosis, endocytosis, lysosomal processing, lipid metabolism, and proliferation in an isoform-specific manner. We further demonstrate that ADAR1 levels and activity are dynamically regulated in adipose tissue and liver during the progression of metabolic disease. Linked to this, macrophage-specific ablation of ADAR1 co-cultured in organotypic 3D primary human liver spheroids and exposed to metabolic stress resulted in an exacerbated lipid accumulation phenotype. Finally, we identify a lipid-associated macrophage-specific upregulation of ADAR1 in adipose tissue following weight loss interventions, mechanistically driven by free fatty acids. These findings uncover a previously unrecognized role for ADAR1 in lipid-buffering, scavenging, and proliferative macrophage functions, extending its biological relevance beyond canonical interferon-mediated immunity and establishing ADAR1 as a key regulator of macrophage adaptation in metabolic disease.