Role of RNA helicases in circRNA biogenesis and regulation

RNA helicases are fundamental ATP-dependent enzymes that remodel RNA structures and ribonucleoprotein complexes. Recent studies reveal that RNA helicases are critical regulators of circular RNA networks, where circRNAs function as stable regulators of gene expression with important implications in disease. This study integrates structural, mechanistic, and functional insights into how RNA helicase families regulate circRNA biogenesis, stability, and function. Accumulating evidence demonstrates that RNA helicases can suppress circRNA biogenesis by remodeling intronic structures, such as DHX9 suppression, or promote biogenesis through DDX5/DDX17, which resolve inhibitory intronic structures by recruiting splicing factors (QKI, SRSF1) and stabilizing spliceosome assembly. We also highlight helicase-mediated control of circRNA stability and decay, such as EIF4A3, DDX5, and DDX17 protecting circRNAs from degradation by blocking decay factors, as well as reciprocal regulation in which circRNAs scaffold to modulate translation. In this review, we summarize RNA helicase families structures and circRNA biogenesis mechanisms, explore their extensive roles in circRNA regulation, and propose RNA helicases as central regulators and promising therapeutic targets, offering new avenues for biomarker development and RNA-based therapies.