RNA G-quadruplexes in gene regulation, human disease, and emerging therapeutic strategies

RNA structural biology has uncovered RNA G-quadruplexes (rG4s) as one of the most versatile and functionally relevant non-canonical structures in post-transcriptional regulation. These guanine-rich motifs, capable of forming stable G-tetrads through Hoogsteen hydrogen bonding, are widely distributed across untranslated regions, coding sequences, long non-coding RNAs, and viral genomes. Over the last decade, transcriptome-wide and single-molecule studies have revealed that rG4s act as dynamic regulatory switches determining translation efficiency, RNA localization, and interactions with RNA-binding proteins. Despite significant advances, key mechanistic questions remain unresolved - how rG4s fold in living cells, how helicases unwind them, and how these processes integrate into broader RNA regulatory networks. Furthermore, growing evidence links rG4 dysfunction to human disease and viral infection, highlighting the pressing need to deepen our understanding of rG4 roles in both physiology and pathology.This Research Topic aims to integrate structural, mechanistic, and translational insights into rG4 biology by bridging fundamental and applied research. The central goal is to clarify the folding principles, recognition mechanisms, and biological functions of rG4 elements within the cell, while exploring how their physiological and pathological dynamics can be therapeutically manipulated. Specifically, this collection seeks to identify how rG4 structures influence RNA metabolism, to define the molecular logic of helicase-mediated resolution, and to understand their contribution to RNP granule formation and neuronal or viral pathophysiology. Contributions addressing the design and characterization of chemical and oligonucleotide-based rG4 modulators are also encouraged to advance preclinical applications.To gather further insights into the diversity and relevance of rG4s in gene expression and disease contexts, we welcome studies that cover the full scale of experimental, computational, and translational approaches, while remaining focused on RNA-mediated regulation. Eligible article types include Original Research, Reviews, Methods, Hypothesis and Theory, and Perspectives.We welcome contributions addressing, but not limited to, the following themes:• Structure, folding thermodynamics, and kinetics of RNA G-quadruplex formation• Helicase mechanisms (DHX36, DHX9) and rG4 resolution in translation control• rG4 interactions with RNA-binding proteins and their role in RNP complex assembly• Transcriptome-wide mapping and computational prediction of functional rG4 sites• rG4 roles in stress granule assembly and biomolecular condensate dynamics• Neurological and viral systems where rG4 misfolding or misregulation contributes to diseaseSmall-molecule and oligonucleotide strategies targeting rG4 structures for therapeutic intervention Topic editors: Cyril Dominguez, Frederic S. W. Arendrup Source: https://www.frontiersin.org/research-topics/83380/rna-g-quadruplexes-in-gene-regulation-human-disease-and-emerging-therapeutic-strategies