dsRNA: mechanisms of gene expression regulation, disease pathogenesis, and therapeutic potential

Double-stranded RNA (dsRNA) has long been recognized as a viral pathogen-associated molecular pattern that activates innate immunity. However, dsRNA is increasingly recognized as a regulatory RNA species involved in RNA homeostasis, gene expression, and cell fate determination. In this review, we discuss canonical dsRNA-dependent mechanisms, including RNA interference (RNAi), with particular emphasis on nuclear RNAi, and dsRNA-sensing networks, together with broader RNA-RNA duplex-associated regulatory processes. We also consider structurally distinct RNA-DNA hybrids that functionally converge with dsRNA-responsive innate immune pathways. We further examine how dysregulation of dsRNA production, processing, sensing, and clearance contributes to cancer, autoimmune disorders, and neurodegenerative diseases, and how these mechanisms can be therapeutically exploited. Collectively, these insights establish a conceptual framework for understanding the roles of dsRNA in physiological regulation, disease pathogenesis, and therapeutic applications.